J. Org. Chem. 1996, 61, 2413-2427
2413
Formal Total Syntheses of the β-Lactam Antibiotics Thienamycin and PS-5 Peter A. Jacobi,* Shaun Murphree, Frederic Rupprecht, and Wanjun Zheng Hall-Atwater Laboratories, Wesleyan University, Middletown, Connecticut 06459-0180 Received November 28, 1995X
Chiral nonracemic acetylenic acids of general structure 11, prepared using the Schreiber modification of the Nicholas reaction, have been converted to β-amino acid derivatives of type 12 by a two-step sequence involving Curtius rearrangement followed by oxidative cleavage of the acetylenic bond. Amino acid derivatives 12 are excellent precursors for β-lactams of the carbapenem class, including the important antibiotics thienamycin (1) and PS-5 (4). Introduction Thienamycin (1) is a member of the carbapenem class of antibiotics, which was initially isolated in 1976 from Streptomyces cattleya,1a and whose structure was determined by an elegant combination of degradative, spectral, and X-ray crystallographic studies (Figure 1).1b Interest in 1 derives from its broad spectrum of antibacterial activity, which includes excellent response against both Gram-(+)- and Gram-(-)-bacteria, as well as certain β-lactamase-producing species. This range of activity is exceptional among members of the β-lactam family of antibiotics, whether naturally occurring or semisynthetic. Imipenem (2), the N-formimidoyl derivative of 1, is currently marketed in a formulation containing a β-lactamase inhibitor.1c A variety of related carbapenem-type β-lactam antibiotics have been isolated and characterized during the past 10-15 years, some of which have antibacterial activity approaching that of 1. These include side-chain deoxygenated compounds, such as PS-5 (4) and PS-6 (5),2 and members of the olivanic acid class of antibiotics, such as MM-22381 (6).3 MM-22381 (6) is isolated from Streptomyces olivaceus and differs from thienamycin (1) in having the S-configuration at C8. In addition, various synthetic analogs, such as 1β-methylcarbapenem (3), have attracted considerable attention because of their increased chemical stability and resistance to dehydropeptidase-I (DHP-I).4 The broad spectrum activity of thienamycin (1) and other potent carbapenem antibiotics, taken together with their challenging structural features, has fostered intense and varied synthetic efforts in this area. These studies are important since 1 cannot be efficiently produced in culture, and both 1 and 2 are currently manufactured by total synthesis.5 Abstract published in Advance ACS Abstracts, March 1, 1996. (1) (a) Kahan, J. S.; Kahan, F. M.; Stapley, E. O.; Goegelman, R. T.; Hernandez, S. U.S. Patent 3950357, 1976; Chem. Abstr. 1976, 85, 92190t. See also: Kahan, J. S.; Kahan, F.; Goegelman, R.; Currie, S. A.; Jackson, M.; Stapely, E. O.; Miller, T. W.; Miller, A. K.; Hendlin, D.; Mochales, S.; Hernandez, S.; Woodruff, H. B.; Birnbaum, J. J. Antibiot. 1979, 32, 1. (b) Albers-Scho¨nberg, G.; Arison, B. H.; Hensens, O. D.; Hirshfield, J.; Hoogsteen, K.; Kaczka, E. A.; Rhoads, R. E.; Kahan, J. S.; Kahan, F. M.; Ratcliffe, R. W.; Walton, E.; Ruswinkle, L. J.; Morin, R. B.; Christensen, B. G. J. Am. Chem. Soc. 1978, 100, 6491. (c) Leanza, W. J.; Wildonger, K. J.; Miller, T. W.; Christensen, B. G. J. Med. Chem. 1979, 22, 1435. (2) (a) Yamamoto, K.; Yoshioka, T.; Kato, Y.; Shibamoto, N.; Okamura, K.; Shimauchi, Y.; Ishikura, T. J. Antibiot. 1980, 33, 796. For references to early syntheses of PS-5 (4), see: (b) Wasserman, H. H.; Han, W. T. Tetrahedron Lett. 1984, 25, 3747 (cf. also ref 12i and references cited therein). (3) Corbett, D. F.; Coulton, S.; Southgate, R. J. Chem. Soc., Perkin Trans. 1 1982, 3011 and references cited therein. X
0022-3263/96/1961-2413$12.00/0
Figure 1.
Figure 2.
Most of the reported syntheses of 1 involve as a key step the preparation of 6-substituted azetidinones of type 7 (X ) leaving group), followed by additional elaboration at N4 and C5 (carbapenem numbering) (Figure 2).6 This approach has the advantage of being highly convergent, and the requisite azetidinones 7 are accessible utilizing [2 + 2] cycloaddition methodology.6 Alternatively, considerable effort has also been devoted to the synthesis of (4) (a) Shih, D. H.; Baker, F.; Cama, L.; Christensen, B. G. Heterocycles 1984, 21, 29. (b) Hatanaka, M. Tetrahedron Lett. 1987, 28, 83. (c) Udodong, U. E.; Fraser-Reid, B. J. Org. Chem. 1989, 54, 2103. (d) Kawabata, T.; Kimura, Y.; Ito, Y.; Terashima, S.; Sasaki, A.; Sunagawa, M. Tetrahedron 1988, 44, 2149 and references cited therein. Kaga, H.; Kobayashi, S.; Ohno, M. Tetrahedron Lett. 1989, 30, 113. (e) Rama Rao, A. V.; Gurjar, M. K.; Khare, V. B.; Ashok, B.; Deshmukh, M. N. Tetrahedron Lett. 1990, 31, 271. (5) (a) Melillo, D. G.; Cvetovich, R. J.; Ryan, K. M.; Sletzinger, M. J. Org. Chem. 1986, 51, 1498. (b) Melillo, D. G.; Shinkai, I.; Liu, T.; Ryan, K.; Sletzinger, M. Tetrahedron Lett. 1980, 21, 2783. (c) Melillo, D. G.; Liu, T.; Ryan, K.; Sletzinger, M.; Shinkai, I. Tetrahedron Lett. 1981, 22, 913. (d) Liu, T. M. H.; Melillo, D. G.; Ryan, K. M.; Shinkai, I.; Setzinger, M. U.S. Patent 4,349,687, 1982, Merck & Co. (6) (a) Karady, S.; Amato, J. S.; Reamer, R. A.; Weinstock, L. M. J. Am. Chem. Soc. 1981, 103, 6765. (b) Barrett, A. G. M.; Quayle, P. J. Chem. Soc., Chem. Commun. 1981, 1076. (c) Greengrass, C. W.; Nobbs, M. S. Tetrahedron Lett. 1981, 22, 5339. (d) Greengrass, C. W.; Hoople, D. W. T. Tetrahedron Lett. 1981, 22, 5335. (e) Reider, P. J.; Rayford, R.; Grabowski, E. J. Tetrahedron Lett. 1982, 23, 379. (f) Koller, W.; Linkies, A.; Pietsch, H.; Rehling, H.; Reuschling, D. Tetrahedron Lett. 1982, 23, 1545. (g) Reider, P. J.; Grabowski, E. J. J. Tetrahedron Lett. 1982, 23, 2293. (h) Aratani, M.; Sawada, K.; Hashimoto, M. Tetrahedron Lett. 1982, 23, 3921. (i) Kraus, G. A.; Neuenschwander, K. J. Chem. Soc., Chem. Commun. 1982, 134. (j) Kametani, T.; Kanaya, N.; Mochizuki, T.; Honda, T. Heterocycles 1982, 19, 1023. (k) Fujimoto, K.; Iwano, Y.; Hirai, K. Tetrahedron Lett. 1985, 26, 89. (l) Hua, D. H.; Verma, A. Tetrahedron Lett. 1985, 26, 547. (m) Tijima, Y.; Yoshida, A.; Takeda, N.; Oida, S. Tetrahedron Lett. 1985, 26, 637. (n) Chiba, T.; Nagatsuma, M.; Nakai, T. Chem. Lett. 1985, 1343. (o) Fliri, H.; Mak, C.-P. J. Org. Chem. 1985, 50, 3438. (p) Meyers, A. I.; Sowin, T. J.; Scholz, S.; Ueda, Y. Tetrahedron Lett. 1987, 28, 5103. (q) Sowin, T. J.; Meyers, A. I. J. Org. Chem. 1988, 53, 4154.
© 1996 American Chemical Society
2414
J. Org. Chem., Vol. 61, No. 7, 1996 Scheme 1
Jacobi et al.
Schreiber reaction for preparing chiral, enantiomerically pure acetylenic acids of general structure 11 and ent-11 (Scheme 1; ent ) mirror image of compound shown).13 Acetylenic acids 11/ent-11 were then converted to protected β-amino acids 12/ent-12 by a two-step sequence involving Curtius rearrangement,14 followed by oxidative cleavage of the acetylenic bond.15 The considerable synthetic potential of this methodology derives from its highly convergent nature and the fact that both relative and absolute stereochemistry at all stereogenic centers can be readily controlled.16 These studies culminated in efficient formal total syntheses of thienamycin (1) and PS-5 (4). Discussion and Results
β-amino acid precursors such as 8. Recent approaches include (a) addition of ester enolates or silylketene acetals to imines;7 (b) Michael addition of amines to unsaturated esters;8 (c) 1,3-dipolar cycloaddition of nitrones to alkenes;9 and (d) hydrogenation of acrylic acid derivatives,10 among others.11,12 In these examples the 5-substituent is generally introduced prior to cyclization of the β-lactam ring. In principle, this approach is applicable to the synthesis of a broader range of substrates, and it formed the basis of the first commercial synthesis of 1.5 However, in many cases absolute stereochemistry is difficult to control. In this paper we describe a new approach to β-amino acids of type 8 which takes advantage of a Nicholas(7) (a) Ha, D.-C.; Hart, D. J.; Yang, T.-K. J. Am. Chem. Soc. 1984, 106, 4819. (b) Shibasaki, M.; Iimori, T. Tetrahedron Lett. 1985, 26, 1523. (c) Cainelli, G.; Contento, M.; Giacomini, D.; Panunzio, M. Tetrahedron Lett. 1985, 26, 937. (d) Hatakana, M.; Nitta, H. Tetrahedron Lett. 1987, 28, 69. (e) Yamada, T.; Suzuki, H.; Mukaiyama, T. Chem. Lett. 1987, 293. (f) Gennari, C.; Venlurini, S.; Gislon, G.; Schimperna, G. Tetrahedron Lett. 1987, 28, 227. (g) Kunz, H.; Schanzenbach, D. Angew. Chem., Int. Ed. Engl. 1989, 28, 1068. (h) Corey, E. J.; Decicco, C. P.; Newbold, C. N. Tetrahedron Lett. 1991, 32, 5287. (8) (a) d’Angelo, J.; Maddaluno, J. J. Am. Chem. Soc. 1986, 108, 8112. (b) Estermann, H.; Seebach, D. Helv. Chim. Acta 1988, 71, 1824. (c) Davies, S. G.; Ichihara, O. Tetrahedron Asymmetry 1991, 2, 183. (9) (a) Kametani, T.; Chu, S.-D.; Honda, T. J. Chem. Soc., Perkin Trans. 1 1988, 1593. (b) Ihara, M.; Takahashi, M.; Fukumoto, K.; Kametani, T. J. Chem. Soc., Perkin Trans. 1 1989, 2215. (10) (a) Lubell, W. D.; Kitamura, M.; Noyori, R. Tetrahedron Asymmetry 1991, 2, 543. (b) Potin, D.; Dumas, F.; d’Angelo, J. J. Am. Chem. Soc. 1990, 112, 3483. (11) (a) Andres, C.; Gonzalez, A.; Pedrosa, R.; Perez-Encabo, A. Tetrahedron Lett. 1992, 33, 2895 and references cited therein. (b) Juaristi, E.; Quintana, D. Tetrahedron Lett. 1992, 33, 723 and references cited therein. (c) Amoroso, R.; Cardillo, G.; Tomasini, C. Tetrahedron Lett. 1992, 33, 2725 and references cited therein. (12) For recent reviews on the synthesis of thienamycin (1) and related materials, see: (a) Nagahara, T.; Kametani, T. Heterocycles 1987, 25, 729. (b) Georg, G. I. In Studies in Natural Product Chemistry; Rahman, A-ur, Ed.; Elsevier Science: Amsterdam, 1989; Vol. 4. (c) Bateson, J. H. In Progress in Heterocyclic Chemistry; Suschitzky, H., Scriven, E. F. V., Eds.; Pergamon Press: Oxford, 1991; Vol. 3. See also: (d) Hanessian, S.; Desilets, D.; Bennani, Y. L. J. Org. Chem. 1990, 55, 3098 and references cited therein. (e) Grieco, P. A.; Flynn, D. L.; Zelle, R. E. J. Am. Chem. Soc. 1984, 106, 6414. (f) Melillo, D. G.; Cvetovich, R. J.; Ryan, K. M.; Sletzinger, M. J. Org. Chem. 1986, 51, 1498. (g) Evans, D. A.; Sjogren, E. B. Tetrahedron Lett. 1986, 27, 4961. (h) Corbett, D. F.; Coulton, S.; Southgate, R. J. Chem. Soc., Perkin Trans. 1 1982, 3011 and references cited therein. (i) Evans, D. A.; Sjogren, E. B. Tetrahedron Lett. 1986, 27, 3119. (j) Yamamoto, K.; Yoshioka, T.; Kato, Y.; Shibamoto, N.; Okamura, K.; Shimauchi, Y.; Ishikura, T. J. Antibiot. 1980, 33, 796. (k) Shono, T.; Kise, N.; Sanda, F.; Ohi, S.; Yoshioka K. Tetrahedron Lett. 1989, 30, 1253. (l) Melillo, D. G.; Cvetovich, R. J.; Ryan, K. M.; Sletzinger, M. J. Org. Chem. 1986, 51, 1498 and references cited therein. (m) Evans, D. A.; Bartroli, J. Tetrahedron Lett. 1982, 23, 807. (n) Georg, G. I.; Akgu¨n, E. Tetrahedron Lett. 1990, 31, 3267. (o) Chackahamannil, S.; Fett, N.; Kirkup, M.; Afonso, A.; Ganguly, A. K. J. Org. Chem. 1988, 53, 450. (p) Salzmann, T. N.; Ratcliffe, R. W.; Christensen, B. G.; Bouffard, F. A. J. Am. Chem. Soc. 1980, 102, 6161. For an alternative synthesis of β-lactams involving intramolecular alkylation, see: (q) Wasserman, H. H.; Hlasta, D. J. Tetrahedron Lett. 1979, 20, 549.
I. Model Studies with Simple Nicholas Substrates (R ) Me). a. Synthesis of Homochiral Acetylenic Acids. The Nicholas reaction takes advantage of the fact that cobalt complexes of general structure 14 greatly facilitate the heterolytic cleavage of adjacent alcohols or ethers,13 which upon HBF413b or Lewis acid13e catalysis afford cobalt-stabilized carbocations of type 15 (Figure 3). Capture of these carbocations with nucleo-
Figure 3.
philes such as electron-rich aromatics,13a ketone or ester enolates,13d,e and enol ethers13c then affords the products of nucleophilic displacement 16, which can be conveniently cleaved to the parent acetylenes 17 under a variety of mild oxidative conditions.13c This methodology avoids complications arising from the formation of allenic byproducts, which frequently predominate upon direct displacement of propargyl tosylates and halides.13f Since propargyl alcohols are readily derived by addition of acetylides to carbonyl compounds, the overall transfor(13) (a) Lockwood, R. F.; Nicholas, K. M. Tetrahedron Lett. 1977, 18, 4163. (b) Nicholas, K. M.; Nestle, M. O.; Seyferth, D. In Transition Metal Organometallics in Organic Synthesis; Alper, H., Ed.; Academic Press: New York, 1978; Vol. 2, p 1. (c) Schreiber, S. L.; Sammakia, T.; Crowe, W. E. J. Am. Chem. Soc. 1986, 108, 3128. (d) Nicholas, K. M.; Mulvaney, M.; Bayer, M. J. Am. Chem. Soc. 1980, 102, 2508. (e) Hodes, H. D.; Nicholas, K. M. Tetrahedron Lett. 1978, 19, 4349. (f) Bramwell, A. F.; Crombie, L.; Knight, M. H. Chem Ind. (London) 1965, 1265 and references cited therein. (g) Saha, M.; Bogby, B.; Nicholas, K. M. Tetrahedron Lett. 1986, 27, 915. (h) Schreiber, S. L.; Klimas, M. T.; Sammakia, T. J. Am. Chem. Soc. 1987, 109, 5749. (14) (a) Shioiri, T.; Ninomiya, K.; Yamada, S. J. Am. Chem. Soc. 1972, 94, 6203. (b) Benalil, A.; Roby, P.; Carboni, B.; Vaultier, M. Synthesis, 1991, 787. (15) (a) Pappo, R.; Allen, D. S., Jr.; Lemieux, R. U.; Johnson, W. S. J. Org. Chem. 1956, 21, 478. (b) Moriarty, R. M.; Penmasta, R.; Awasthi, A. K.; Prakash, I. J. Org. Chem. 1988, 53, 6164 and references cited therein. (16) For previous papers in this series see: (a) Jacobi, P. A.; Guo, J. Tetrahedron Lett. 1995, 36, 2717. (b) Jacobi, P. A.; Guo, J.; Zheng, W. Tetrahedron Lett. 1995, 36, 1197. (c) Jacobi, P. A.; Brielmann, H. L.; Hauck, S. I. Tetrahedron Lett. 1995, 36, 1193. (d) Jacobi, P. A.; Zheng, W. Tetrahedron Lett. 1993, 34, 2581. (e) Jacobi, P. A.; Zheng, W. Tetrahedron Lett. 1993, 34, 2585. (f) Jacobi, P. A.; Rajeswari, S. Tetrahedron Lett. 1992, 33, 6231; (g) 1992, 33, 6235. (g) Jacobi, P. A; DeSimone, R. W. Tetrahedron Lett. 1992, 33, 6239.
Total Syntheses of Thienamycin and PS-5
J. Org. Chem., Vol. 61, No. 7, 1996 2415 Table 1 yield,a no.
compd
%
[R]25D (c)d
compd
yield,a %
[R]25D (c)d
1 2 3 4 5
24a ent-24a 24b 24c ent-24c
94b 80c 20b 93b 78c
+28.7 (12.4) -26.0 (30.6) +15.9 (4.5) -33.1 (6.4) +37.4 (14.7)
25a ent-25a 25b 25c ent-25c
91 91 56 86 79
+11.7 (27.8) -11.5 (60.7) -1.3 (45.8) -31.6 (7.8) +30.2 (19.5)
a Average yield for several runs. b Yield employing 2 equiv of 22. c Yield employing 1 equiv of 22. d Measured in MeOH (c ) mg/ mL).
Scheme 3 Figure 4.
Scheme 2
Scheme 4
mation constitutes a flexible carbonyl-to-geminal dialkyl transposition. In 1987, Schreiber et al. described the first example of a Nicholas reaction involving a homochiral nucleophile. Thus, alkylation of boron enolate 18 with cobalt complex 19 afforded a 12:1 mixture of syn-adduct 20s together with the corresponding 2,3-anti-isomer 20a (Figure 4; 20a not shown).13h Oxidative cleavage of 20s with cerric ammonium nitrate (CAN) then gave an excellent yield of the parent acetylene 21s. This result was rationalized on the basis of a novel double stereodifferentiating process, in which the racemic carbocation derived from 19 interconverts via enantiomerization at a rate which is fast relative to alkylation (kinetic resolution).13h In principle, this observation provides the basis for a general synthesis of homochiral acetylenic acid derivatives that might find widespread utility in organic synthesis. However, until recently little was known about the effect of chiral substituents on such transformations.16 In order to explore the generality of the NicholasSchreiber methodology, we initially studied the preparation of acetylenic acids 25a-c (Scheme 2). Cobalt derivatives 23a-c were readily obtained by condensation of lithio(trimethylsilyl)acetylene with the appropriate aldehydes R′CHMeCHO (R′ ) H, Me, S-OBn), followed by in situ methylation (DMS),16 and complexation of the resulting methylpropargyl ethers with Co2(CO)8.13 Imide enolate 22 was prepared following the general procedure of Schreiber et al.,13h employing 1.0 equiv each of (iC3H7)2NEt and Bu2BOTf at 0 °C in CH2Cl2. The resulting enolate solutions were then cooled to -78 °C, treated with an additional 0.5-1.0 equiv of Bu2BOTf, followed by an equimolar quantity of 23 (based on excess Bu2BOTf), and warmed to 0 °C to afford the desired adducts 24 after oxidative cleavage with CAN (Table 1). In identical fashion, imide enolate ent-22 afforded the enantiomeric adducts ent-24 upon condensation with cobalt complexes ent-23 (Scheme 3).
In general, yields for this reaction were excellent (8598%), utilizing a ratio of 22:23 ) 2:1 (entries 1 and 4, Table 1), and only slightly less satisfactory (75-85%), employing a ratio of 22:23 ) 1:1 (entries 2 and 5, Table 1). Not surprisingly, however, 24b (R′ ) Me) was obtained in considerably lower yield (20%, entry 3, Table 1), presumably due to steric hindrance and competing elimination reactions in the stabilized carbocation derived from 23b.13 Diastereo- and enantioselectivities were also generally excellent, with syn:anti ratios of >98:2 employing chiral enolates 22 and ent-22 with achiral cobalt complexes 23a,b (entries 1-3, Table 1; slightly lower syn-selectivity was observed employing chiral enolates 18 and ent-18; cf. Figure 4). Equally impressive ratios (>98:2) were obtained with the “matched” chiral substrates 22 + 23c f 25c, and ent-22 + ent-23c f ent-24c (entries 4 and 5, Table 1; the case of “mismatched” substrates will be discussed below). These results are in full accord with the transition state model proposed by Schreiber et al. (vide supra).13h Once in hand, oxazolidinones 24/ent-24 were readily converted to the corresponding acetylenic acids 25/ent25 by hydrolysis with excess lithium hydroperoxide,17 which effected concomitant cleavage of the TMS group (Scheme 2). As indicated (Table 1), yields for this step were excellent (80-98%), except for the special case where R′ ) Me (entry 3, Table 1). In this example, steric hindrance once again had a deleterious effect on reactivity. Finally, 5R,6R-diastereoselectivity of >98:2 was also obtained upon condensation of chiral cobalt complex 23c with the achiral enolate 26 (Scheme 4), as judged by conversion of the derived adduct 27c to the identical homochiral acetylenic acid 25c obtained employing chiral enolate 22 (cf. Scheme 2).18 This result provides some (17) Evans, D. A.; Britton, T. C.; Ellman, J. A. Tetrahedron Lett. 1987, 28, 6141. (18) We are grateful to Ms. Gayle Schulte, of Yale University, for carrying out an X-ray analysis of acetylenic acid 25c.
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Jacobi et al.
Table 2 yield,a no. compd 1 2 3 4 5
28a ent-28a 28b 28c ent-28c
yield,a
%
[R]25D (c)b
compd
%
[R]25D (c)b
82 74 64 92 82
+61.1 (24.8) -64.0 (20.1) +55.2 (20.4) +34.9 (19.8) -34.4 (4.7)
30a ent-30a 30b 30c ent-30c
97 92 86 68 68
+12.7 (2.7) -13.8 (7.2) +23.8 (15.1) +62.4 (16.3) -64.7(12.8)
no.
compd
yield,a %
[R]25D (c)c
1 2 3 4 5
32a ent-32a 32b 32c ent-32c
71 81 82 76 83
+19.8 (10.3) -18.3 (19.5) +11.3 (23.0) +35.5 (19.8) -36.5 (10.5)
a Average yield for several runs. b Measured in MeOH (c ) mg/ mL). c Measured in CH2Cl2 (c ) mg/mL).
afford pure 30a,b in >90% overall yield (entries 1 and 3, Table 2). With 28c (R′ ) OBN), however, KMnO4/NaIO4 caused extensive decomposition due to oxidation of the benzyl protecting group to give benzoic acid. This difficulty was eventually circumvented with our finding that OsO4/NaIO4 provided the desired chemoselectivity,15 leading exclusively to the N-formyl derivative 29c. As with 29a,b described above, 29c was then readily cleaved with KOH to afford the desired carbamate 30c (entry 4, Table 2). The utility of these amino acid derivatives for the synthesis of β-lactams was then convincingly demonstrated by their facile conversion to amino acids 31a-c and subsequently to lactams 32a-c upon cyclization with dicyclohexylcarbodiimide (DCC).12e Finally, in identical fashion, acetylenic acids ent-25a,c were converted in four steps to the enantiomeric β-lactams ent-32a,c (Scheme 6), which were also obtained as single isomers (entries 2 and 5, Table 2). Scheme 6
Figure 5.
indication of the powerful directing influence which chiral substituents can exert on the Nicholas reaction. b. Conversion of Acetylenic Acids 25/ent-25 to β-Amino Acids 30/ent-30 and β-Lactams 32/ent-32. We next studied the conversion of acetylenic acids 25 to homochiral amino acid derivatives 30 (Scheme 5). As
II. Formal Synthesis of PS-5. β-Lactam 32a (cf. Scheme 5) bears a close structural resemblance to the known alcohol derivative 33 (5R,6R-stereochemistry), which has previously been employed in the synthesis of the potent antibiotic PS-5 (4) (Figure 6).19 We envisioned
Scheme 5
Figure 6.
that precursors of type 33 might be conveniently prepared using methodology analogous to that described in Schemes 2 and 5. In order to explore this possibility it was first necessary to prepare the chiral oxazolidinone derivative 39, which was derived in excellent overall yield beginning with 1,4-butanediol (34) (Scheme 7). Thus, indicated, Curtius rearrangement of 25 to afford carbamates 28 was conveniently carried out with diphenyl phosphorazidate (DPPA),14a followed by HCl-catalyzed capture of the intermediate isocyanate (not isolated) with 2-methyl-2-propanol.14b Within the limits of detection, this step occurred with complete retention of stereochemistry, as determined by NMR analysis and comparison of the specific rotations for 28a,c and ent-28a,c (Table 2). However, we experienced some initial difficulties in effecting the oxidative cleavage of acetylenic carbamates 28 to the desired amino acid derivatives 30. For 28a,b, this transformation was best accomplished with KMnO4/ NaIO4,12e which afforded ∼50:50 mixtures of the corresponding acids 30a,b together with the N-formyl derivatives 29a,b. We believe that formyl derivatives 29 were derived by intramolecular formylation involving oxidation intermediates of type I (Figure 5), since 30 itself was unreactive to formic acid. In any event, these mixtures were usually not separated, but rather were directly hydrolyzed (KOH) to
Scheme 7
selective monoprotection of 34 with TBDPSCl gave a 90% yield of the corresponding alcohol 35, which upon oxidation with PDC in DMF afforded carboxylic acid derivative 36 in 75% yield. Treatment of 36 with oxalyl chloride in benzene then provided the acid chloride 37 (99%), which (19) (a) Tanner, D.; Somfai, P. Tetrahedron 1988, 44, 619. See also: (b) Shono, T.; Kise, N.; Sanda, F.; Ohi, S.; Yoshioka, K. Tetrahedron Lett. 1989, 30, 1253.
Total Syntheses of Thienamycin and PS-5 Scheme 8
Figure 7.
Scheme 9
was directly converted to the desired acyl derivative 39 by condensation with the lithium anion derived from oxazolidinone 38 (89% yield from 36).20 Once in hand, oxazolidinone 39 was readily converted to the corresponding boron enolate (vide supra),13h which underwent smooth Nicholas condensation with cobalt complex 23a to give syn-adduct 40 in 88% overall yield after decomplexation (Scheme 8; >98:2 syn-selectivity). Surprisingly, however, hydrolysis of 40 under the standard conditions (LiOOH, 3:1 THF/H2O) afforded complex mixtures of products,17 consisting in part of endo-ringopened alcohol 41, together with lesser amounts of the desired carboxylic acid 42 derived by exo-hydrolysis (conditions A). This unexpected reaction pathway might be due to complexation of Li cation between the exocarbonyl group and the -OTBDPS functionality (cf. II, Figure 7), since related alkyl derivatives (OTBDPS ) Me) underwent normal hydrolysis (vide infra). In any event, addition of DMF to the hydrolysis reaction completely reversed the regioselectivity (3:3:1 DMF/THF/H2O) and afforded an 81% yield of the desired acetylenic acid 42 with no trace of endo-ring opened product 41 (conditions B). We believe that DMF functions by solvating chelated intermediates of type II-IV (Figure 7), themselves
J. Org. Chem., Vol. 61, No. 7, 1996 2417
derived by initial coordination of Li cation with adduct 40 (40 f II). This result is in qualitative agreement with the suggestion of Evans et al. that the rate-determining step in cleavage by HOO- is collapse of the initially formed tetrahedral intermediate.17 In the case of endoattack (II f III), collapse of intermediate III to 41 is presumably accelerated by chelation of the type illustrated in III, which renders the oxazolidinone C-N bond relatively labile. In contrast, intermediate IV, derived by exo-attack (II f IV), is most likely stabilized by chelation. Therefore, collapse of IV to the desired carboxylic acid 42 is relatively slow. As expected on the basis of this hypothesis, DMF had no effect on the regioselectivity of hydrolysis by HO-, where the ratedetermining step is formation of the tetrahedral intermediate (steric control).17 In both cases (with and without added DMF), hydrolytic cleavage was predominantly endocyclic to afford 41. The remaining steps necessary for the conversion of 42 to the PS-5 (4) precursor 33 were then accomplished in a straightforward fashion, in exact analogy to our model studies described in Scheme 5. Thus, Curtius rearrangement of 42 with DPPA afforded an 83% yield of the carbamate derivative 43,14 which upon oxidative cleavage with KMnO4/NaIO4 gave the desired protected amino acid 44 in 91% yield (Scheme 9). This last compound, upon TFA-catalyzed deprotection, then gave a quantitative yield of the β-amino acid 45, which in turn afforded 91% of the target β-lactam 33 upon cyclization with DCC. The material thus prepared had chemical and physical properties identical to those reported in the literature19a and was obtained as a single enantiomer. III. Formal Synthesis of Thienamycin. a. Model Studies with Matched and Mismatched Substrates. In Schemes 2 and 5 we described an efficient synthesis of β-amino acid derivative 31c, making use of a “matched” condensation of oxazolidinone enolate 22 with cobalt complex 23c (Figure 8). Amino acid 31c has the 5R,6S,8S-
Figure 8.
stereochemistry characteristic of MM-22381 (6) (cf. Figure 1), and it served as a useful probe of stereochemical control in the Nicholas reaction. As employed in this case, the term “matched” refers to those condensations in which the chirality of the oxazolidinone precursor reinforces the directing effect of the C-8 stereogenic center in cobalt complexes 23. As previously noted (Scheme 4), chiral cobalt complex 23c combines even with achiral oxazolidinone 26 to provide adduct 27c with excellent diastereo- and enantioselectivity. On the basis of these results, it was of interest to determine if a similar approach could be applied to the synthesis of amino acids having the 5R,6S,8R-configuration found in thienamycin (1) (cf. Figure 1).1 In principle, this substitution pattern was available by “mismatched” condensation of oxazolidinone 39 with cobalt complex ent-23c (Figure 9). This combination (20) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem Soc. 1981, 103, 2127.
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Figure 9.
Scheme 10
Scheme 11
Jacobi et al.
exact analogy to our earlier studies with 30c and ent30c (P ) CO2t-Bu; cf. Schemes 5 and 6). Upon cyclization of 51 to β-lactam 53 the cis-relationship between H5-H6 was immediately apparent from their relatively large coupling constant (J5,6 ) 6.0 Hz) (Scheme 11). For trans-β-lactams this coupling constant is typically 98:2 syn-selectivity. In contrast to the case with 22, oxazolidinone ent-18 underwent clean “mismatched” condensation with ent23c to provide an ∼12:1 mixture of two isomeric acetylenic acid derivatives (Scheme 10). These were subsequently identified as syn-adduct 48s and anti-isomer 48a. Interestingly, however, the major isomer proved to be the anti-adduct 48a, as demonstrated by chemical correlation (it was impossible to distinguish between 48s and 48a on the basis of spectral data alone). Thus, 48a was readily converted to the carboxylic acid 49a,17 which upon Curtius rearrangement (81%)14 followed by oxidative cleavage (71%)15 afforded amino acid derivative 51a in
that ent-23c combines with achiral oxazolidinones to provide syn-adducts of 5S,6S,8R-stereochemistry, the incorrect configuration at C5 and C6; cf. Scheme 4). As in the case with 40 (cf. Scheme 8), hydrolysis of 57 under standard conditions (LiOOH, 3:1 THF/H2O) afforded a complex mixture of products,17 from which endo-ring opened product 58 could be isolated in 30% yield (condi(21) Chiba, T.; Nakia, T. Tetrahedron Lett. 1985, 26, 4647.
Total Syntheses of Thienamycin and PS-5 Scheme 13
tions A). No trace of the desired carboxylic acid 59 derived from exo-nucleophilic attack could be detected. Once again, however, addition of DMF to the hydrolysis reaction completely reversed the regioselectivity (3:3:1 DMF/THF/H2O) and afforded a 74% yield of the desired acetylenic acid 59 together with only traces of 58 (conditions B). As described above for 49 (cf. Scheme 10), 59 was then converted in two steps to the homochiral amino acid derivative 61, which upon deprotection and cyclization with DCC afforded the cis-β-lactam 62 in 56% yield (Scheme 13). Finally, epimerization of 62 according to the procedure of Nakai et al. afforded the known thienamycin precursor 63,12e,21 which had spectral data identical to that reported by Grieco et al. for the racemic material.22 Summary The control of relative and absolute stereochemistry at three and more contiguous centers is an important problem in organic synthesis. In some cases we believe that the Nicholas reaction could provide an attractive alternative to more traditional methodology in this area. This will be especially true for molecules containing carboxylate, alkene, amino, and related functionalities which are easily derived from acetylenic acid derivatives of type 11. To illustrate this potential, we have developed unequivocal syntheses of two of the most important members of the carbapenem class of antibiotics. Extension of this methodology to the synthesis of other biologically important molecules is currently under investigation.
Experimental Section Melting points were determined in open capillaries and are uncorrected. 1H NMR spectra were recorded at either 200 or 400 MHz and are expressed as ppm downfield from tetramethysilane. General Procedure for the Preparation of Methyl Propargylic Ethers. A solution of (trimethylsilyl)acetylene (1.0 equiv) in THF was cooled to -78 °C under nitrogen and was treated in a dropwise fashion, with vigorous stirring, with 2.5 M n-butyllithium/hexanes (1.0 equiv). The resulting mixture was stirred at -78 °C for an additional 10 min and was then treated over 5 min with a solution of the desired aldehyde (1.0 equiv) in THF. After the mixture was stirred for an additional 15 min, dimethyl sulfate (1.0 equiv) was added to the mixture and the cooling bath was removed. The reaction mixture was then stirred at rt for 18-48 h and monitored by TLC. When complete, the reaction was quenched by addition of 140 mL of saturated aqueous NH4Cl, and the separated aqueous layer was extracted with 3 × 100 mL of (22) We are grateful to Professor Paul Grieco, of Indiana University, for providing an NMR spectra of (()-63 (cf. ref 12e).
J. Org. Chem., Vol. 61, No. 7, 1996 2419 diethyl ether. The combined organic layers were dried (MgSO4), filtered, and concentrated under reduced pressure. Purification by either chromatography or distillation then afforded the methyl propargylic ether. General Procedure for the Preparation of Hexacarbonyldicobalt-Complexed Alkynes 23a-c. A solution of octacarbonyldicobalt (1.05 or 1.1 equiv) in anhydrous diethyl ether was stirred at rt under nitrogen and was treated in a dropwise fashion with a solution of the desired methyl propargylic ether (1.0 equiv) in anhydrous diethyl ether (see above). The resulting mixture was then stirred at rt for 3-8 h. Following this period, the solvent was concentrated under reduced pressure, and the residue was chromatographed to afford the corresponding cobalt-complexed alkyne. 3-Methoxy-1-(trimethylsilyl)pentyne, Hexacarbonyldicobalt Complex (23a). 3-Methoxy-1-(trimethylsilyl)pentyne was prepared following the general procedure described above, using 12.1 mL (86.2 mmol, 1.0 equiv) of (trimethylsilyl)acetylene in 350 mL of THF, 34.3 mL (1.0 equiv) of 2.5 M n-butyllithium/hexanes, 6.20 mL (1.0 equiv) of propionaldehyde, and 8.10 mL (1.0 equiv) of dimethyl sulfate. After the mixture was stirred at rt for 23 h, isolation and distillation gave 12.5 g (85%) of 3-methoxy-1-(trimethylsilyl)pentyne as a colorless oil, bp 65-67 °C/18 mm: IR (CH2Cl2) 2966, 2168, 1675, 1463, 1334, 1252, 1132, 1052 cm-1; 1H NMR (CDCl3) δ 0.16 (s, 9H), 0.97 (t, J ) 7.0 Hz, 3H), 1.68 (m, 2H), 3.38 (s, 3H), 3.85 (t, J ) 7.0 Hz, 1H). Following the general procedure described above, a solution of 1.90 g (11.1 mmol, 1.0 equiv) of 3-methoxy-1-(trimethylsilyl)pentyne in 10 mL of diethyl ether and 4.00 g (11.7 mmol, 1.05 equiv) of octacarbonyldicobalt in 60 mL of diethyl ether was stirred for 3.5 h at rt. Concentration and chromatography (100:1 hexanes/EtOAc) then afforded 4.90 g (96%) of 23a as a dark solid: IR (CH2Cl2) 2962, 2096, 2059, 2026, 1671, 1562 cm-1; 1H NMR (CDCl3) δ 0.32 (bs, 9H), 1.11 (bs, 3H), 1.76 (bs, 2H), 3.56 (bs, 3H), 4.50 (bs, 1H). 3-Methoxy-4-methyl-1-(trimethylsilyl)pentyne, Hexacarbonyldicobalt Complex (23b). 3-Methoxy-4-methyl-1(trimethylsilyl)pentyne was prepared following the general procedure described above, using 12.1 mL (86.2 mmol, 1.0 equiv) of (trimethylsilyl)acetylene in 250 mL of THF, 34.3 mL (1.0 equiv) of 2.5 M n-butyllithium/hexanes, 7.80 mL (1.0 equiv) of 2-methylpropionaldehyde, and 8.10 mL (1.0 equiv) of dimethyl sulfate. After the mixture was stirred at rt for 36 h, isolation and distillation gave 13.0 g (82%) of 3-methoxy4-methyl-1-(trimethylsilyl)pentyne as a colorless oil, bp 7779 °C/21 mm: MS m/e 169 (M+ - Me), 141, 126, 113, 97, 89, 83, 59; IR (CH2Cl2) 2963, 2168, 1469, 1349, 1250, 1088, 1028 cm-1; 1H NMR (CDCl3) δ 0.20 (s, 9H), 1.00 (t, J ) 7.5 Hz, 6H), 1.92 (m, 1H), 3.42 (s, 3H), 3.72 (d, J ) 6.5 Hz, 1H); 13C NMR (CDCL3) δ 0.08, 17.65, 18.39, 32.80, 56.52, 77.29, 90.89, 103.40. Anal. Calcd for C10H20OSi: C, 65.15; H, 10.93. Found: C, 65.25; H, 10.94. Following the general procedure described above, a solution of 2.05 g (11.1 mmol, 1.0 equiv) of 3-methoxy4-methyl-1-(trimethylsilyl)pentyne in 10 mL of diethyl ether and 4.00 g (11.7 mmol, 1.05 equiv) of octacarbonyldicobalt in 55 mL of diethyl ether was stirred for 3.5 h at rt. Concentration and chromatography (100:1 hexanes/EtOAc) then afforded 5.05 g (99%) of 23b as a dark solid: IR (CH2Cl2) 2962, 2087, 2047, 2021, 1578, 1270, 1088 cm-1; 1H NMR (CDCl3) δ 0.32 (s, 9H), 1.06 (d, J ) 7.5 Hz, 3H), 1.10 (d, J ) 7.5 Hz, 3H), 1.88 (m, 1H), 3.54 (s, 3H), 3.98 (d, J ) 6.0 Hz, 1H). 4(S)-(Benzyloxy)-3-methoxy-1-(trimethylsilyl)pentyne, Hexacarbonyldicobalt Complex (23c). 4(S)-(Benzyloxy)-3-methoxy-1-(trimethylsilyl)pentyne was prepared following the general procedure described above, using 3.50 mL (24.5 mmol, 1.0 equiv) of (trimethylsilyl)acetylene in 100 mL of THF, 9.80 mL (1.0 equiv) of 2.5 M n-butyllithium/hexanes, 4.02 g (1.0 equiv) of 2-(S)-(benzyloxy)propionaldehyde in 20 mL of THF, and 2.30 mL (1.0 equiv) of dimethyl sulfate. After the mixture was stirred at rt for 22 h, isolation and chromatrography (20:1 hexanes/EtOAc) gave 6.64 g (98%) of 4(S)(benzyloxy)-3-methoxy-1-(trimethylsilyl)pentyne as a colorless oil: MS m/e 232 (M+ - 44), 217, 201, 185, 170, 155, 141, 135, 123, 113; IR (CH2Cl2) 3033, 2962, 2170, 1453, 1252, 1098, 1028 cm-1; 1H NMR (CDCl3) δ 0.21 (s, 9H), 1.29 (d, J ) 6.5 Hz, 3H), 3.45 (s, 3H), 3.67 (m, 1H), 4.02 (m, 1H), 4.67 (m, 2H), 7.27-
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7.41 (m, 5H). Anal. Calcd for C16H24O2Si: C, 69.52; H, 8.75. Found: C, 69.65; H, 8.76. Following the general procedure described above, a solution of 2.00 g (7.23 mmol, 1.0 equiv) of 4(S)-(benzyloxy)-3-methoxy-1-(trimethylsilyl)pentyne in 10 mL of diethyl ether and 2.70 g (1.1 equiv) of octacarbonyldicobalt in 38 mL of diethyl ether was stirred for 3.5 h at rt. Concentration and chromatography (100:1 hexanes/EtOAc) then afforded 3.86 g (95%) of 23c as a dark liquid: IR (CH2Cl2) 3050, 2957, 2088, 2049, 2022, 1585, 1454, 1376, 1101 cm-1; 1 HNMR (CDCl3) δ 0.28 (two s, 9H), 1.26 (d, J ) 6.5 Hz, 3H), 1.32 (d, J ) 6.5 Hz, 3H), 3.60 (s, 3H), 3.45-3.75 (m, 1H), 4.274.70 (m, 3H), 7.24-7.40 (m, 5H). 4(R)-(Benzyloxy)-3-methoxy-1-(trimethylsilyl)pentyne, Hexacarbonyldicobalt Complex (ent-23c). This material was prepared in 98% yield from 4.62 g of 4(R)(benzyloxy)-3-methoxy-1-(trimethylsilyl)pentyne following the same procedure as that described above for 23c. Cobalt complex ent-23c had spectral data identical to that provided for 23c. General Procedures for the Nicholas Reaction and Oxidative Decomplexation. Method A. A solution consisting of 11.0 mmol (2.0 equiv) of the appropriate oxazolidone in 37 mL of anhydous methylene chloride was cooled to 0 °C under nitrogen and was treated in dropwise fashion, with vigorous stirring, with 2.0 equiv of freshly distilled N,Ndiisopropylethylamine and 2.0 equiv of a 1.0 M solution of dibutylboron triflate/methylene chloride. After the mixture was stirred for 15 min at 0 °C, an additional 1.0 equiv of dibutylboron triflate was added and the resulting mixture was cooled to -78 °C. A solution consisting of 5.50 mmol (1.0 equiv) of the appropriate cobalt-complexed alkyne in 15 mL of methylene chloride was then added in dropwise fashion and with vigorous stirring. After the addition was complete, the resulting mixture was allowed to warm to 0 °C, and stirring was continued for 20 min each at 0 °C and at rt, respectively. The reaction was then quenched with 90 mL of ice-cold pH 7 buffer, and the separated aqueous layer was extracted with 3 × 40 mL of methylene chloride. The combined organic extracts were dried (MgSO4), filtered, concentrated under reduced pressure, and chromatographed (20:1 or 10:1 hexanes/EtOAc) to afford the desired cobalt complexed Nicholas adduct together with excess oxazolidone. The crude material thus obtained was dissolved in 100 mL of acetone and treated portionwise, at rt and with vigorous stirring, with ammonium cerium(IV) nitrate (CAN) until gas evolution ceased. A slight excess of CAN was then added, and the solvent was removed under reduced pressure at rt. The resultant residue was partitioned between 70 mL of water and 55 mL of diethyl ether, and the separated aqueous layer was extracted with 5 × 55 mL of diethyl ether. The combined organic layers were dried (MgSO4), filtered, concentrated under reduced pressure, and chromatographed (20:1 or 10:1 hexanes/EtOAc) to give the desired product. Method B. Method B was identical to method A but employed equimolar quantities of the appropriate oxazolidones and cobalt-complexed acetylenes. Nicholas Adduct 24a. Following method A, above, a solution of 2.03 g (11.0 mmol, 2.0 equiv) of (S)-4-isopropyl-Npropionyl-2-oxazolidone (22) in 37 mL of CH2Cl2, 1.89 mL of i-Pr2NEt, 11.0 and 5.50 mL (2.0 and 1.0 equiv) of 1.0 M Bu2BOTf/CH2Cl2, a solution of 2.50 g (1.0 equiv) of the cobaltcomplexed alkyne 23a in 15 mL of CH2Cl2, and 100 mL of acetone with excess CAN gave 1.66 g (94%) of adduct 24a as a light yellow oil: [R]25D +28.7° (c ) 12.4, MeOH); MS m/e 323 (M+), 308, 194, 179, 151, 130, 97, 73; IR (CH2Cl2) 2967, 2167, 1778, 1701, 1386, 1208 cm-1; 1H NMR (CDCl3) δ 0.12 (s, 9H), 0.92 (t, J ) 7.0 Hz, 6H), 1.03 (t, J ) 7.5 Hz, 3H), 1.17 (d, J ) 7.5 Hz, 3H), 1.40 (m, 1H), 1.56 (m, 1H), 2.38 (m, 1H), 2.73 (m, 1H), 3.98 (quint, J ) 7.0 Hz, 1H), 4.20 (dd, J ) 3.5, 6.5 Hz, 1H), 4.27 (t, J ) 8.5 Hz, 1H), 4.41 (m, 1H); 13C NMR (CDCl3) δ -0.3, 11.0, 13.8, 14.6, 17.5, 23.1, 28.1, 36.2, 40.9, 57.9, 62.7, 85.7, 107.8, 153.1, 174.6; HRMS(CI) calcd for (C17H29NO3Si + H) ([M + H]+) 324.1995, found 324.2012. Nicholas Adduct ent-24a. Following method B, above, a solution of 1.87 g (10.1 mmol, 1.0 equiv) of (R)-4-isopropyl-Npropionyl-2-oxazolidone (ent-22) in 33 mL of CH2Cl2, 1.74 mL
Jacobi et al. of i-Pr2NEt, 10.1 and 10.1 mL (1.0 and 1.0 equiv) of 1.0 M Bu2BOTf/CH2Cl2, a solution of 4.60 g (1.0 equiv) of the cobalt complexed alkyne ent-23a in 27 mL of CH2Cl2, and 60 mL of acetone with excess CAN gave 2.61 g (80%) of adduct ent-24a as a light yellow oil: [R]25D -26.0° (c ) 30.6, MeOH); IR and 1 H NMR are identical to those of adduct 24a. Nicholas Adduct 24b. Following method A, above, a solution of 4.21 g (22.7 mmol, 2.0 equiv) of (S)-4-isopropyl-Npropionyl-2-oxazolidone (22) in 80 mL of CH2Cl2, 3.93 mL of i-Pr2NEt, 22.7 and 11.4 mL (2.0 and 1.0 equiv) of 1.0 M Bu2BOTf/CH2Cl2, a solution of 5.35 g (1.0 equiv) of the cobaltcomplexed alkyne 23b in 15 mL of CH2Cl2, and 50 mL of acetone with excess CAN gave 0.76 g (20%) of adduct 24b as a white solid, mp 93.0-93.5 °C (hexanes, colorless needles): [R]25D +15.9° (c ) 4.5, MeOH); MS m/e 337 (M+), 322, 294, 208, 193, 165, 130, 123; IR (CH2Cl2) 2966, 2168, 1778, 1700, 1465, 1386, 1251, 1207 cm-1; 1H NMR (CDCl3) δ 0.10 (s, 9H), 0.93 (m, 9H), 1.04 (d, J ) 7.0 Hz, 3H), 1.12 (d, J ) 7.5 Hz, 3H), 1.90 (m, 1H), 2.42 (m, 1H), 2.73 (dd, J ) 2.9, 10.8 Hz, 1H), 4.04 (m, 1H), 4.23 (m, 2H), 4.48 (m, 1H); 13C NMR (CDCl3) δ 0.1, 14.6, 15.3, 16.1, 21.8, 26.6, 39.4, 42.3, 54.7, 78.4, 87.5, 105.6, 125.5, 128.6, 133.4, 152.4, 176.0. Anal. Calcd for C18H31NO3Si: C, 64.05; H, 9.26; N, 4.15. Found: C, 63.85; H, 9.31; N, 4.09. Nicholas Adduct 24c. Following method A, above, a solution of 8.89 g (48.0 mmol, 2.0 equiv) of (S)-4-isopropyl-Npropionyl-2-oxazolidone (22) in 180 mL of CH2Cl2, 8.28 mL of i-Pr2NEt, 48.0 and 24.0 mL (2.0 and 1.0 equiv) of 1.0 M Bu2BOTf/CH2Cl2, a solution of 13.5 g (1.0 equiv) of the cobaltcomplexed alkyne 23c in 45 mL of CH2Cl2, and 250 mL of acetone with excess CAN gave 9.56 g (93%) of adduct 24c as a pale yellow oil: [R]25D -33.1° (c ) 6.4, MeOH); MS m/e 370 (M+ - 59), 294, 256, 245, 202, 165, 123, 91; IR (CH2Cl2) 3062, 2968, 2170, 1780, 1700, 1385, 1256, 1206, 1097 cm-1; 1H NMR (CDCl3) δ 0.12 (s, 9H), 0.92 (d, J ) 7.5 Hz, 6H), 1.05 (d, J ) 6.8 Hz, 3H), 1.35 (d, J ) 6.2 Hz, 3H), 2.39 (m, 1H), 2.89 (dd, J ) 3.1, 10.3 Hz, 1H), 3.73 (m, 1H), 4.15-4.48 (m, 4H), 4.47 (d, J ) 12.2 Hz, 1H), 4.67 (d, J ) 12.2 Hz, 1H), 7.23-7.42 (m, 5H); 13C NMR (CDCl3) δ 0.0, 15.0, 15.6, 17.0, 17.9, 28.4, 39.2, 41.0, 58.3, 62.9, 69.8, 72.0, 87.3, 105.5, 127.2, 127.4, 128.1, 138.5, 153.2, 175.5; HRMS(CI) calcd for (C24H35NO4Si + H) ([M + H]+) 430.2415, found 430.2398. Nicholas Adduct ent-24c. Following method B, above, a solution of 1.67 g (9.02 mmol, 1.0 equiv) of (R)-4-isopropyl-Npropionyl-2-oxazolidone (ent-22) in 30 mL of CH2Cl2, 1.55 mL of i-Pr2NEt, 9.0 and 9.0 mL (1.0 and 1.0 equiv) of 1.0 M Bu2BOTf/CH2Cl2, a solution of 5.07 g (1.0 equiv) of the cobalt complexed alkyne ent-23c in 25 mL of CH2Cl2, and 100 mL of acetone with excess CAN gave 3.04 g (78%) of the adduct ent24c as a pale yellow oil: [R]25D +37.4° (c ) 14.7, MeOH); IR and 1H NMR are identical to those of adduct 24c. Nicholas Adduct 27c. Following method A, above, a solution of 0.91 g (34.9 mmol, 2.0 equiv) of N-propionyl-2oxazolidone (26) in 123 mL of CH2Cl2, 5.53 mL of i-Pr2NEt, 34.9 and 17.5 mL (2.0 and 1.0 equiv) of 1.0 M Bu2BOTf/CH2Cl2, a solution of 9.82 g (1.0 equiv) of the cobalt-complexed alkyne 23c in 34 mL of CH2Cl2, and 250 mL of acetone with excess CAN gave 6.30 g (93%) of the adduct 27c as a pale yellow oil: [R]25D -66.9° (c ) 9.2, CH2Cl2); MS m/e 372 (M+ - 15), 328, 256, 252, 192, 165, 160, 143, 123, 97, 91; IR (CH2Cl2) 3031, 2967, 2171, 1782, 1701, 1480, 1454, 1385, 1250, 1221, 1106, 1044 cm-1; 1H NMR (CDCl3) δ 0.10 (s, 9H), 1.10 (d, J ) 6.9 Hz, 3H), 1.31 (d, J ) 6.3 Hz, 3H), 2.80 (dd, J ) 9.3 , 3.3 Hz, 1H), 3.77 (m, 2H), 3.92 (m, 1H), 4.13 (m, 1H), 4.28 (m, 2H), 4.39 (d, J ) 12.0 Hz, 1H), 4.62 (d, J ) 12.0 Hz, 1H), 7.31 (m, 5H); 13C NMR (CDCl3) δ 0.0, 15.6, 17.0, 38.1, 42.4, 42.6, 61.5, 69.9, 73.0, 88.2, 104.8, 127.3, 127.4, 128.1, 138.6, 153.0, 175.7; HRMS(CI) calcd for (C21H29NO4Si + H) ([M + H]+) 388.1944, found 388.1936. Nicholas Adduct ent-27c. Following method A, above, a solution of 0.91 g (6.33 mmol, 2.0 equiv) of N-propionyl-2oxazolidone (26) in 22 mL of CH2Cl2, 1.10 mL of i-Pr2NEt, 6.33 and 3.16 mL (2.0 and 1.0 equiv) of 1.0 M Bu2BOTf/CH2Cl2, a solution of 1.78 g (1.0 equiv) of the cobalt-complexed alkyne ent-23c in 6.3 mL of CH2Cl2, and 50 mL of acetone with excess CAN gave 1.01 g (83%) of the adduct ent-27c as a pale yellow
Total Syntheses of Thienamycin and PS-5 oil: [R]25D +63.5° (c ) 17.1, CH2Cl2); 1HNMR and IR are identical to those of adduct 27c. Nicholas Adducts 48a and 48s. Following method A, above, a solution of 3.22 g (13.8 mmol, 2.0 equiv) of (S)-4methyl-(R)-5-phenyl-N-propionyl-2-oxazolidone (ent-18) in 60 mL of CH2Cl2, 2.35 mL of i-Pr2NEt, 13.8 and 6.90 mL (2.0 and 1.0 equiv) of 1.0 M Bu2BOTf/CH2Cl2, a solution of 3.88 g (1.0 equiv) of the cobalt-complexed alkyne ent-23c in 15 mL of CH2Cl2, and 100 mL of acetone with excess CAN gave 2.68 g (81%) of adduct 48a and 0.24 g (7%) of adduct 48s. Analytical data for 48a: mp 96.5-97.0 °C (hexanes, colorless cotton-like crystals); [R]25D -27.6° (c ) 3.5, MeOH); IR (CH2Cl2) 3032, 2963, 2170, 1780, 1698, 1496, 1456, 1346, 1197, 1121 cm-1; 1H NMR (CDCl3) δ 0.17 (s, 9H), 0.65 (d, J ) 6.7 Hz, 3H), 1.36 (d, J ) 6.5 Hz, 6H), 3.36 (dd, J ) 5.0, 9.5 Hz, 1H), 3.67 (quint, J ) 5.5 Hz, 1H), 4.20 (quint, J ) 8.0 Hz, 1H), 4.42 (d, J ) 12.5 Hz, 1H), 4.50 (d, J ) 12.5, 1H), 4.72 (quint, J ) 7.0 Hz, 1H), 6.62 (d, J ) 7.5 Hz, 1H), 7.22-7.42 (m, 10H). Anal. Calcd for C28H35NO4Si: C, 70.41; H, 7.39; N, 2.93. Found: C, 70.48; H, 7.40; N, 2.89. Analytical data for 48s: mp 117.0-117.5 °C (pentane, colorless cotton-like crystals); [R]25D +1.9° (c ) 13.3, CH2Cl2); IR (CH2Cl2) 3033, 2974, 2170, 1780, 1703, 1456, 1344, 1250, 1198, 1121 cm-1; 1H NMR (CDCl3) δ 0.18 (s, 9H), 0.77 (d, J ) 6.6 Hz, 3H), 1.31 (d, J ) 7.0 Hz, 3H), 1.40 (d, J ) 6.1 Hz, 3H), 3.13 (t, J ) 7.2 Hz, 1H), 3.74 (quint, J ) 6.2 Hz, 1H), 4.15 (m, 1H), 4.49 (d, J ) 11.9 Hz, 1H), 4.57 (d, J ) 11.9, 1H), 4.80 (quint, J ) 6.7 Hz, 1H), 5.67 (d, J ) 7.6 Hz, 1H), 7.23-7.47 (m, 10H). Anal. Calcd for C28H35NO4Si: C, 70.41; H, 7.39; N, 2.93. Found: C, 70.48; H, 7.42; N, 2.89. 1-O-(tert-Butyldiphenylsilyl)-1,4-butanediol (35). A solution of 6.0 g (66.6 mmol, 3.0 equiv) of 1,4-butanediol in 35 mL of THF was cooled to -78 °C under nitrogen, and the resulting white suspension was treated in dropwise fashion, with vigorous stirring, with 8.9 mL (22.2 mmol, 1.0 equiv) of 2.5 M n-butyllithium/hexanes. The reaction mixture became very viscous. After being stirred for additional 5 min, the reaction mixture was treated in dropwise fashion with 5.76 mL (22.2 mmol, 1.0 equiv) of TBDPSCl, and the resulting mixture was allowed to warm to rt to give a white suspension. After being stirred at rt for 40 min, the reaction mixture was treated with 35 mL of water and 35 mL of saturated aqueous NH4Cl solution, and the separated aqueous layer was extracted with 3 × 50 mL of diethyl ether. The combined organic extracts were dried (MgSO4), filtered, concentrated under reduced pressure, and chromatographed (100:15 hexanes/ EtOAc) to yield 6.58 g (90%) of 35 as a colorless oil: IR (CH2Cl2) 3616, 3436, 3048, 2933, 2859, 1472, 1427, 1390, 1267, 1111, 1056 cm-1; 1H NMR (CDCl3) δ 1.06 (s, 9H), 1.67 (m, 4H), 3.68 (m, 4H), 7.37-7.69 (m, 10H). 4-[(tert-Butyldiphenylsilyl)oxy]butyric Acid (36). A solution of 5.70 g (17.4 mmol, 1.0 equiv) of 35 in 45 mL of DMF was cooled to 0 °C under nitrogen and was treated portionwise with 22.9 g (60.7 mmol, 3.5 equiv) of PDC. The resulting mixture was allowed to warm to rt and was stirred overnight (15 h). The reaction was then poured into a separatory funnel containing 320 mL of water and extracted with 5 × 180 mL of diethyl ether. The combined organic extracts were dried (MgSO4), filtered, concentrated under reduced pressure, and chromatographed (100:5 hexanes/EtOAc and 75:25:0.3 hexanes/EtOAc/AcOH) to afford 4.43 g (75%) of 36 as a colorless oil: IR (CH2Cl2) 3288-2500, 1749, 1711, 1472, 1428, 1288, 1111 cm-1; 1H NMR (CDCl3) δ 1.07 (s, 9H), 1.91 (quint, J ) 6.6 Hz, 2H), 2.53 (t, J ) 7.4 Hz, 2H), 3.73 (t, J ) 6.0 Hz, 2H), 7.36-7.69 (m, 10H); 13CNMR (CDCl3) δ 19.2, 26.8, 27.5, 30.8, 62.8, 127.6, 129.6, 133.6, 135.5, 180.1. 4-[(tert-Butyldiphenylsilyl)oxy]butyryl Chloride (37). A solution of 4.77 g (13.9 mmol, 1.0 equiv) of 36 in 48 mL of benzene was treated with 6.9 mL (79.4 mmol, 5.7 equiv) of oxalyl chloride at rt, and the reaction was stirred at rt for 6 h. The solvent and excess oxalyl chloride were then removed under reduced pressure to afford a quantitative yield of acid chloride 37 as a pale yellow, unstable oil: IR (CH2Cl2) 3072, 2932, 1797, 1472, 1428, 1112 cm-1; 1H NMR (CDCl3) δ 1.07 (s, 9H), 1.95 (quint, J ) 6.0 Hz, 2H), 3.07 (t, J ) 7.2 Hz, 2H), 3.70 (t, J ) 5.7 Hz, 2H), 7.38-7.68 (m, 10H).
J. Org. Chem., Vol. 61, No. 7, 1996 2421 4(S)-Isopropyl-N-[4′-[(tert-butyldiphenylsilyl)oxy]butyryl-2-oxazolidone (39). A solution of 0.55 g (4.29 mmol, 1.0 equiv) of (S)-4-isopropyl-2-oxazolidone (38) in 55 mL of THF was cooled to -78 °C under nitrogen and was treated in dropwise fashion, with vigorous stirring, with 1.72 mL (1.0 equiv) of 2.5 M n-butyllithium/hexanes. After being stirred for an additional 10 min at -78 °C, the reaction was treated with a solution of 1.55 g (1.0 equiv) of acid chloride 37 in 10 mL of THF. The reaction mixture was then allowed to warm slowly to rt and was treated with 50 mL of saturated aqueous NH4Cl solution. The aqueous layer was extracted with 3 × 50 mL of diethyl ether, and the combined organic extracts were dried (MgSO4), filtered, concentrated, and chromatographed (10:1 hexanes/EtOAc) to afford 1.74 g (89%) of 39 as a colorless oil: [R]25D +40.6° (c ) 8.4, CH2Cl2); MS m/e 396 (M+ - CMe3), 324, 318, 310, 267, 224, 199, 181, 161, 135, 105; IR (CH2Cl2) 3072, 2963, 2932, 2859, 1780, 1702, 1472, 1428, 1387, 1302, 1208, 1112, 1022, 971, 909 cm-1; 1H NMR (CDCl3) δ 0.83 (d, J ) 6.9 Hz, 3H), 0.87(d, J ) 7.2 Hz, 3H), 1.02 (s, 9H), 1.90 (quint, J ) 6.8 Hz, 2H), 2.33 (m, 1H), 3.03 (t, J ) 7.4 Hz, 2H), 3.70 (t, J ) 6.3 Hz, 2H), 4.18 (m, 2H), 4.37 (m, 1H), 7.32-7.65 (m, 10H). Anal. Calcd for C26H35NO4Si: C, 68.84; H, 7.78; N, 3.09. Found: C, 68.67; H, 7.86; N, 2.95. 4(S)-Methyl-5(R)-phenyl-N-[4′-[(tert-butyldiphenylsilyl)oxy]butyryl-2-oxazolidone (56). A solution of 2.47 g (13.9 mmol, 1.0 equiv) of 4(S)-methyl-5(R)-phenyl-2-oxazolidone (38b) in 180 mL of THF was cooled to -78 °C under nitrogen and was treated in dropwise fashion, with vigorous stirring, with 5.60 mL (1.0 equiv) of 2.5 M n-butyllithium/ hexanes. After being stirred for an additional 10 min at -78 °C, the reaction mixture was treated with a solution of 5.03 g (1.0 equiv) of acid chloride 37 in 30 mL of THF. The resulting light brown solution was stirred for 20 min at -78 °C, warmed to 0 °C, and stirred for 20 min at 0 °C. The reaction mixture was then treated with 50 mL of saturated aqueous NH4Cl and 10 mL of water, and the aqueous layer was extracted with 3 × 60 mL of diethyl ether. The combined organic extracts were dried (MgSO4), filtered, concentrated, and chromatographed (silica gel; 100:5 hexanes/EtOAc) to afford 5.22 g (75%) of 56 as a colorless oil: [R]25D -17.8° (c ) 18.1, CH2Cl2); IR (CH2Cl2) 3071, 2932, 1781, 1703, 1472, 1428, 1348, 1198, 1111, 1032 cm-1; 1H NMR (CDCl3) δ 0.88 (d, J ) 7.0 Hz, 3H), 1.08 (s, 9H), 1.96 (quint, J ) 7.0 Hz, 2H), 3.09 (t, J ) 7.4 Hz, 2H), 3.74 (t, J ) 6.2 Hz, 2H), 4.73 (quint, J ) 6.9 Hz, 1H), 5.62 (d, J ) 7.3 Hz, 1H), 7.28-7.69 (m, 15H); 13C NMR (CDCl3) δ 14.6, 19.2, 26.9, 27.0, 32.3, 54.7, 62.9, 78.8, 125.5, 127.6, 128.6, 129.5, 133.3, 133.7, 135.5, 152.9, 172.7. Nicholas Adduct 40. A solution of 1.50 g (3.31 mmol, 2.0 equiv) of 4(S)-isopropyl-N-[4-[(tert-butyldiphenylsilyl)oxy]butyryl]-2-oxazolidone (39) in 12 mL of anhydrous methylene chloride was cooled to 0 °C under nitrogen and was treated in dropwise fashion, with vigorous stirring, with 0.57 mL (3.31 mmol, 2.0 equiv) of freshly distilled N,N-diisopropylethylamine and 3.3 mL (3.30 mmol, 2.0 equiv) of a 1.0 M solution of dibutylboron triflate/methylene chloride. After being stirred for 15 min, the reaction mixture was cooled to -78 °C and treated with an additional 1.65 mL (1.65 mmol, 1.0 equiv) of 1.0 M dibutylboron triflate/methylene chloride. A solution of 0.75 g (1.65 mmol, 1.0 equiv) of the cobalt-complexed alkyne 23a in 3.5 mL of methylene chloride was then added in dropwise fashion and with vigorous stirring. The resulting mixture was stirred for 5 min at -78 °C and was then warmed to 0 °C and stirred for 20 min at 0 °C. The reaction was then quenched with 15 mL of pH 7 buffer, and the aqueous layer was extracted with 3 × 15 mL of methylene chloride. The combined organic extracts were dried (MgSO4), filtered, concentrated, and chromatographed (10:1 hexanes/EtOAc) to afford the desired cobalt-complexed product together with a small amount of excess oxazolidone 39. The material thus obtained was dissolved in 50 mL of acetone and treated portionwise, at rt and with vigorous stirring, with ammonium cerium(IV) nitrate (CAN) until gas evolution ceased. The solvent was then concentrated under reduced pressure at rt, and the residue was partitioned between 20 mL of water and 20 mL of diethyl ether. The aqueous layer was extracted with 5 × 20 mL of diethyl ether, and the combined organic extracts
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J. Org. Chem., Vol. 61, No. 7, 1996
were dried (MgSO4), filtered, concentrated, and chromatographed (10:1 hexanes/EtOAc) to give 859 mg (88%) of adduct 40 as a pale yellow oil: [R]25D +14.3° (c ) 2.9, CH2Cl2); IR (CH2Cl2) 3072, 2964, 2932, 2859, 2168, 1777, 1701, 1464, 1428, 1387, 1256, 1204, 1112, 845 cm-1; 1H NMR (CDCl3) δ 0.12 (s, 9H), 0.88 (t, J ) 6.8 Hz, 3H), 1.03 (m, 15H), 1.19-1.54 (m, 2H), 1.96 (m, 1H), 2.07 (m, 1H), 2.33 (m, 1H), 2.76 (m, 1H), 3.66 (m, 2H), 4.01-4.14 (m, 2H), 4.23 (m, 1H), 4.33 (m, 1H), 7.33-7.68 (m, 10 H). Anal. Calcd for C34H49NO4Si2: C, 68.99; H, 8.34; N, 2.37. Found: C, 68.91; H, 8.36; N, 2.36. Nicholas Adduct 57. A solution of 5.03 g (10.0 mmol, 2.0 equiv) of 4(S)-methyl-5(R)-phenyl-N-[4-[(tert-butyldiphenylsilyl)oxy]butyryl]-2-oxazolidone (56) in 35 mL of anhydrous methylene chloride was cooled to 0 °C under nitrogen and was treated in dropwise fashion, with vigorous stirring, with 1.74 mL (10.0 mmol, 2.0 equiv) of freshly distilled N,N-diisopropylethylamine and 10.0 mL (10.0 mmol, 2.0 equiv) of a 1.0 M solution of dibutylboron triflate/methylene chloride. After being stirred for 15 min, the reaction mixture was cooled to -78 °C and treated with an additional 5.00 mL (5.00 mmol, 1.0 equiv) of 1.0 M dibutylboron triflate/methylene chloride. A solution of 2.82 g (5.00 mmol, 1.0 equiv) of the cobaltcomplexed alkyne ent-23c in 10.0 mL of methylene chloride was then added in dropwise fashion and with vigorous stirring. The resulting mixture was stirred for 5 min at -78 °C and was then warmed to 0 °C and stirred for 20 min at 0 °C. The reaction was then quenched with 65 mL of pH 7 buffer, and the aqueous layer was extracted with 3 × 55 mL of methylene chloride. The combined organic extracts were dried (MgSO4), filtered, concentrated, and chromatographed (10:1 hexanes/ EtOAc) to afford the desired cobalt complexed product together with a small amount of excess oxazolidone 56. The material thus obtained was dissolved in 225 mL of acetone and treated portionwise, at rt and with vigorous stirring, with ammonium cerium(IV) nitrate (CAN) until gas evolution ceased. The solvent was then concentrated under reduced pressure at rt, and the residue was partitioned between 90 mL of water and 80 mL of diethyl ether. The aqueous layer was extracted with 5 × 80 mL of diethyl ether, and the combined organic extracts were dried (MgSO4), filtered, concentrated, and chromatographed (10:1 hexanes/EtOAc) to give 2.97 g (79%) of adduct 57 as a pale yellow oil: [R]25D 0.00° (c ) 68.3, CH2Cl2); IR (CH2Cl2) 3055, 2935, 1781, 1704, 1348, 1198, 1112 cm-1; 1H NMR (CDCl3) δ 0.17 (s, 9H), 0.64 (d, J ) 6.5 Hz, 3H), 1.09 (s, 9H), 1.42 (d, J ) 6.2 Hz, 3H), 2.21 (m, 2H), 3.35 (m, 1H), 3.693.88 (m, 3H), 4.37 (m, 1H), 4.46 (d, J ) 12.3 Hz, 1H), 4.52 (d, J ) 12.3 Hz, 1H), 4.53 (m, 1H), 5.16 (d, J ) 6.3 Hz, 1H), 7.137.73 (m, 20 H); 13C NMR (CDCl3) δ 0.1, 14.2, 16.6, 19.2, 27.0, 33.8, 39.3, 40.6, 54.7, 62.0, 70.5, 75.8, 78.3, 89.4, 104.8, 125.5, 127.2, 127.3, 127.5, 127.6, 128.1, 128.4, 129.6, 133.4, 133.7, 133.9, 135.5, 138.7, 152.4, 173.9. Anal. Calcd for C45H55NO5Si2: C, 72.44; H, 7.43; N,1.88. Found: C, 72.70; H, 7.47; N,1.84. General Procedure for the Preparation of Acetylenic Acids by Hydrolysis of N-Acyloxazolidones. A solution of 10.9 mmol (1.0 equiv) of the N-acyloxazolidone in 120 mL of THF and 40 mL of water was cooled to 0 °C with stirring and was treated with 4.0 equiv of 30% aqueous hydrogen peroxide and 2.0 equiv of lithium hydroxide monohydrate. The reaction mixture was then allowed to warm to rt and was stirred overnight (12-17 h) before being cooled back to 0 °C and treated with 32 mL of a 1.5 N sodium sulfite solution. The resulting mixture was warmed to rt, and stirring was continued for 1 h. At the end of this period, the reaction was treated with 140 mL of a saturated aqueous sodium bicarbonate solution, and the THF was evaporated under reduced pressure. The remaining alkaline aqueous solution was then washed with 3 × 50 mL of methylene chloride and acidified to pH ) 1-3 first with concd HCl and then with 5 N aqueous HCl. The resulting suspension was then extracted with 6 × 80 mL of ethyl acetate, and the combined extracts were dried (MgSO4), filtered, concentrated under reduced pressure, and chromatographed (silica gel; 75:25:0.3 hexanes/EtOAc/HOAc) to afford the corresponding acetylenic acid. Acetylenic Acid 25a. This material was prepared in 91% yield following the general procedure described above, employ-
Jacobi et al. ing 3.54 g (10.9 mmol, 1.0 equiv) of N-acyloxazolidone 24a in 120 mL of THF and 40 mL of water, 4.96 g (4.0 equiv) of 30% aqueous hydrogen peroxide, 0.92 g (2.0 equiv) of lithium hydroxide monohydrate for 17 h, 32 mL of 1.5 N sodium sulfite, and 140 mL of saturated aqueous sodium bicarbonate. Chromatography (silica gel; 75:25:0.3 hexanes/EtOAc/HOAc) gave 1.40 g (91%) of 25a as a colorless oil: [R]25D +11.7° (c ) 27.8, MeOH); MS m/e 140 (M+), 125, 111, 97, 83, 74, 67; IR (CH2Cl2) 3303, 3303-2428, 2115, 1748, 1711, 1463, 1416, 1288, 1233 cm-1; 1H NMR (CDCl3) δ 1.06 (t, J ) 7.0 Hz, 3H), 1.27 (d, J ) 7.0 Hz, 3H), 1.46-1.63 (m, 2H), 2.14 (d, J ) 2.0 Hz, 1H), 2.632.74 (m, 2H); 13C NMR (CDCl3) δ 11.8, 13.5, 24.0, 35.9, 43.1, 70.8, 84.6, 181.1; HRMS(CI) calcd for (C8H12O2 + H) ([M + H]+) 141.0916, found 141.0925. Acetylenic Acid ent-25a. This material was prepared in 91% yield following a procedure identical to that described above for acetylenic acid 25a, employing 2.58 g (7.98 mmol, 1.0 equiv) of N-acyloxazolidone ent-24a in 87 mL of THF and 29 mL of water, 3.62 g (4.0 equiv) of 30% aqueous hydrogen peroxide, 0.67 g (2.0 equiv) of lithium hydroxide monohydrate for 16 h, 23 mL of 1.5 N sodium sulfite, and 102 mL of saturated aqueous sodium bicarbonate. Chromatography (silica gel; 75:25:0.3 hexanes/EtOAc/HOAc) gave 1.02 g (91%) of ent-25a as a colorless oil: [R]25D -11.5° (c ) 60.7, MeOH); IR and 1H NMR are identical to those of acid 25a. Acetylenic Acid 25b. This material was prepared in 56% yield following the general procedure described above, employing 0.83 g (2.45 mmol, 1.0 equiv) of N-acyloxazolidone 24b in 36 mL of THF and 12 mL of water, 1.11 g (4.0 equiv) of 30% aqueous hydrogen peroxide, 0.21 g (2.0 equiv) of lithium hydroxide monohydrate for 2.5 days, 7 mL of 1.5 N sodium sulfite, and 31 mL of saturated aqueous sodium bicarbonate. Chromatography (silica gel; 75:25:0.3 hexanes/EtOAc/HOAc) gave 0.21 g (56%) of 25b as a white solid: mp 68.5-70.0 °C (hexanes, colorless needles); [R]25D -1.3° (c ) 45.8, MeOH); IR (CH2Cl2) 3303, 3303-2562, 1748, 1711, 1462 cm-1; 1H NMR (CDCl3) δ 0.94 (d, J ) 6.6 Hz, 3H), 1.03 (d, J ) 6.6 Hz, 3H), 1.22 (d, J ) 7.0 Hz, 3H), 1.90 (m, 1H), 2.11 (d, J ) 2.4 Hz, 1H), 2.47 (m, 1H), 2.66 (m, 1H). Anal. Calcd for C9H14O2: C, 70.10; H, 9.15. Found: C, 70.11; H, 9.18. Acetylenic Acid 25c. From N-acyloxazolidone 24c: This material was prepared in 86% yield following the general procedure described above, employing 4.00 g (9.31 mmol, 1.0 equiv) of N-acyloxazolidone 24c in 118 mL of THF and 39 mL of water, 4.22 g (4.0 equiv) of 30% aqueous hydrogen peroxide, 0.78 g (2.0 equiv) of lithium hydroxide monohydrate for 18 h, 27 mL of 1.5 N sodium sulfite, and 118 mL of saturated aqueous sodium bicarbonate. Chromatography (silica gel; 75: 25:0.3 hexanes/EtOAc/HOAc) gave 1.97 g (86%) of 25c as a white solid: mp 62.0-62.5 °C (8:1 hexanes/ether, colorless needles); [R]25D -31.6° (c ) 7.8, MeOH); MS m/e 246 (M+), 202, 140, 111, 91, 65; IR (CH2Cl2) 3303, 3302-2550, 1750, 1712, 1455, 1379, 1140, 1082 cm-1; 1H NMR (CDCl3) δ 1.13 (d, J ) 7.0 Hz,3H), 1.37 (d, J ) 6.0 Hz, 3H), 2.20 (d, J ) 2.5 Hz, 1H), 2.66 (m, 1H), 2.84 (quint, J ) 7.5 Hz, 1H), 3.73 (m, 1H), 4.46 (d, J ) 12.0 Hz, 1H), 4.70 (d, J ) 12.0 Hz, 1H), 7.34 (m, 5H). Anal. Calcd for C15H18O3: C, 73.15; H, 7.37. Found: C, 73.22; H, 7.31. From N-acyloxazolidone 27c: 6.30 g (16.26 mmol, 1.0 equiv) of N-acyloxazolidone 27c in 180 mL of THF and 60 mL of water, 7.38 g (4.0 equiv) of 30% aqueous hydrogen peroxide, 0.98 g (2.0 equiv) of lithium hydroxide monohydrate for 18 h, 47 mL of 1.5 N sodium sulfite, and 210 mL of saturated aqueous sodium bicarbonate gave 3.64 g (91%) of 25c as a white solid, having identical physical and spectral properties as those described above: [R]25D -31.7° (c ) 5.5, MeOH). Acetylenic Acid ent-25c. From N-acyloxazolidone ent24c: This material was prepared in 79% yield following the general procedure described above, employing 2.36 g (5.49 mmol, 1.0 equiv) of N-acyloxazolidone ent-24c in 70 mL of THF and 23 mL of water, 2.49 g (4.0 equiv) of 30% aqueous hydrogen peroxide, 0.46 g (2.0 equiv) of lithium hydroxide monohydrate for 16 h, 16 mL of 1.5 N sodium sulfite, and 70 mL of saturated aqueous sodium bicarbonate. Chromatography (silica gel; 75:25:0.3 hexanes/EtOAc/HOAc) gave 1.06 g
Total Syntheses of Thienamycin and PS-5 (79%) of ent-25c: [R]25D +30.2° (c ) 19.5, MeOH). Melting point, IR, and 1H NMR are identical to those of acid 25c. From N-acyloxazolidone ent-27c: 0.406 g (1.05 mmol, 1.0 equiv) of N-acyloxazolidone ent-27c in 12 mL of THF and 4 mL of water, 0.476 g (4.0 equiv) of 30% aqueous hydrogen peroxide, 0.088 g (2.0 equiv) of lithium hydroxide monohydrate for 16 h, 3 mL of 1.5 N sodium sulfite, and 13 mL of saturated aqueous sodium bicarbonate gave 0.242 g (94%) of ent-25c, having physical and spectral properties identical to those described above: [R]25D +28.2° (c ) 14.9, MeOH). Acetylenic Acid 49a. This material was prepared in 85% yield following the general procedure described above, employing 3.25 g (7.56 mmol, 1.0 equiv) of N-acyloxazolidone 48a in 96 mL of THF and 32 mL of water, 3.43 g (4.0 equiv) of 30% aqueous hydrogen peroxide, 0.63 g (2.0 equiv) of lithium hydroxide monohydrate for 16 h, 22 mL of 1.5 N sodium sulfite, and 96 mL of saturated aqueous sodium bicarbonate. Chromatography (silica gel; 75:25:0.3 hexanes/EtOAc/HOAc) gave 1.43 g (85%) of 49a as a pale yellow oil: [R]25D +4.1° (c ) 25.8, MeOH); IR (CH2Cl2) 3303, 3303-2500, 1747, 1706, 1456, 1286, 1065 cm-1; 1H NMR (CDCl3) δ 1.35 (d, J ) 6.5 Hz, 3H), 1.41 (d, J ) 7.0 Hz, 3H), 2.21 (d, J ) 2.5 Hz,1H), 2.86 (m, 1H), 2.95 (m, 1H), 3.69 (m, 1H), 4.49 (d, J ) 11.5 Hz, 1H), 4.50 (d, J ) 11.5 Hz, 1H), 7.25-7.39 (m, 5H); 13CNMR (CDCl3) δ 16.4, 17.3, 39.4, 40.7, 70.9, 72.9, 74.1, 81.4, 127.5, 127.7, 128.2, 138.1, 181.7; HRMS(CI) calcd for (C15H18O3 + H) ([M + H]+) 247.1335, found 247.1337. Acetylenic Acid 49s. This material was prepared in 39% yield following the general procedure described above, employing 0.28 g (0.65 mmol, 1.0 equiv) of N-acyloxazolidone 48s in 8.2 mL of THF and 2.7 mL of water, 0.30 g (4.0 equiv) of 30% aqueous hydrogen peroxide, 0.05 g (2.0 equiv) of lithium hydroxide monohydrate for 16 h, 1.9 mL of 1.5 N sodium sulfite, and 8.2 mL of saturated sodium bicarbonate. Chromatography (silica gel; 75:25:0.3 hexanes/EtOAc/HOAc) gave 62 mg (39%) of 49s as a pale yellow oil: [R]25D -38.6° (c ) 12.2, CH2Cl2); IR (CH2Cl2) 3303, 3303-2400, 1708, 1454, 1376, 1285, 1242, 1111 cm-1; 1H NMR (CDCl3) δ 1.28 (d, J ) 7.5 Hz, 3H), 1.39 (d, J ) 6.5 Hz, 3H), 2.18 (d, J ) 2.5 Hz, 1H), 2.85 (m, 1H), 3.02 (m, 1H), 3.79 (m, 1H), 4.47 (d, J ) 11.5 Hz, 1H), 4.60 (d, J ) 11.5 Hz, 1H), 7.25-7.36 (m, 5H); 13C NMR (CDCl3) δ 13.9, 18.0, 39.4, 42.1, 71.0, 72.2, 74.2, 82.0, 127.5, 127.9, 128.2, 137.9, 180.2. Acetylenic Acid 42. A solution of 859 mg (1.45 mmol, 1.0 equiv) of N-acyloxazolidone 40 in 24 mL of THF, 24 mL of DMF, and 8 mL of water was cooled to 0 °C with stirring and was treated with 1.67 g (10.0 equiv) of 30% aqueous hydrogen peroxide and 304 mg (5.0 equiv) of lithium hydroxide monohydrate. The reaction mixture was then allowed to warm to rt and was stirred overnight (12 h) before being cooled back to 0 °C and treated with 11 mL of 1.5 N sodium sulfite solution. The reaction was then warmed to rt, stirred for an additional 1 h, acidified to pH ) 3 with 5 N aqueous HCl, and extracted with 6 × 40 mL of ethyl acetate. The combined extracts were dried (MgSO4), filtered, and concentrated at rt under high vacuum to remove DMF. The remaining residue was then dissolved in 14 mL of THF and 14 mL of water, and the resulting solution was treated with 304 mg (5.0 equiv) of lithium hydroxide monohydrate at rt for 1 day to complete cleavage of the TMS group. The reaction mixture was then diluted with 10 mL of water, acidified with 5 N aqueous HCl to pH ) 3.5, and extracted with 6 × 30 mL of ethyl acetate. The combined organic extracts were dried (Na2SO4), filtered, concentrated under reduced pressure, and chromatographed (silica gel; 100:10:0.2 hexanes/EtOAc/HOAc) to afford 481 mg (81%) of acetylenic acid 42 as a pale yellow oil: [R]25D +12.4° (c ) 13.4, CH2Cl2); MS m/e 199 (M+ - 209), 181, 139, 135, 123, 105, 91, 77; IR (CH2Cl2) 3304, 3304-2400, 3056, 2964, 2934, 2860, 1747, 1709, 1473, 1428, 1391, 1112 cm-1; 1H NMR (CDCl3) δ 1.05 (m, 12H), 1.55 (m, 2H), 1.88-2.10 (m, 2H), 2.11 (d, J ) 2.4 Hz, 1H), 2.67 (m, 1H), 2.86 (m, 1H), 3.74 (t, J ) 6.0 Hz, 2H), 7.33-7.69 (m, 10H); 13C NMR (CDCl3) δ 12.0, 19.2, 24.9, 26.8, 31.7, 35.6, 45.2, 61.9, 71.1, 84.3, 127.7, 129.7, 133.6, 135.6, 179.4. Anal. Calcd for C25H32O3Si: C, 73.49; H, 7.89. Found: C, 73.55; H, 7.94.
J. Org. Chem., Vol. 61, No. 7, 1996 2423 Acetylenic Acid 59. A solution of 2.16 g (2.89 mmol, 1.0 equiv) of N-acyloxazolidone 57 in 39 mL of THF, 39 mL of DMF, and 13 mL of water was cooled 0 °C with stirring and was treated with 2.63 g (8.0 equiv) of 30% aqueous hydrogen peroxide and 0.48 g (4.0 equiv) of lithium hydroxide monohydrate. The reaction mixture was then allowed to warm to rt and was stirred overnight (20 h) before being cooled back to 0 °C and treated with 17.5 mL of 1.5 N sodium sulfite solution. The reaction was then warmed to rt, stirred for an additional 1 h, diluted with 40 mL of water, acidified to pH ) 2 with 5 N aqueous HCl, and extracted with 6 × 80 mL of ethyl acetate. The combined extracts were dried (MgSO4), filtered, and concentrated at rt under high vacuum to remove DMF. The remaining residue was then dissolved in 27 mL of THF and 27 mL of water, and the resulting solution was treated with 0.73 g (6.0 equiv) of lithium hydroxide monohydrate at rt for two days to complete cleavage of the TMS group. The reaction mixture was then diluted with 40 mL of water, acidified with 5 N aqueous HCl to pH ) 3.5, and extracted with 6 × 60 mL of ethyl acetate. The combined organic extracts were dried (MgSO4), filtered, concentrated under reduced pressure, and chromatographed (silica gel; 100:10:0.2 hexanes/EtOAc/HOAc) to afford 1.06 (74%) of acetylenic acid 59 as a pale yellow oil: [R]25D +9.6° (c ) 25.7, CH2Cl2); IR (CH2Cl2) 3302, 3350-2413, 1746, 1706, 1472, 1428, 1144, 1112 cm-1; 1H NMR (CDCl3) δ 1.05 (s, 9H), 1.35 (d, J ) 6.1 Hz, 3H), 2.01 (m,1H), 2.17 (d, J ) 2.4 Hz, 1H), 2.26 (m, 1H), 2.88 (m, 1H), 3.06 (m, 1H), 3.66 (m, 1H), 3.75 (m,1H), 4.45 (d, J ) 11.8 Hz, 1H), 4.56 (d, J ) 11.8 Hz, 1H), 7.21-7.70 (m, 15H); 13C NMR (CDCl3) δ 17.5, 19.2, 26.8, 33.6, 40.4, 42.2, 61.9, 71.0, 73.1, 74.3, 81.5, 127.5, 127.6, 128.3, 129.6, 133.4, 133.5, 135.6, 138.2, 179.8; HRMS(CI) calcd for (C32H38O4Si + H) ([M + H]+) 515.2619, found 515.2642. General Procedures for the Curtius Rearrangement of Acetylenic Acids. Method A. A solution consisting of 5.56 mmol (1.0 equiv) of the appropriate acetylenic acid in 32 mL of benzene was treated in dropwise fashion, and with vigorous stirring, with 1.0 equiv each of DPPA and triethylamine at rt under a nitrogen atmosphere. After addition was complete, the reaction mixture was heated at reflux for 3.5 h, and the solvent was evaporated under reduced pressure. The residue was taken up in 32 mL of t-BuOH containing 0.1 equiv of CuCl, and the resulting mixture was heated at reflux under nitrogen for 1-2 h before t-BuOH was removed under reduced pressure. The remaining residue was partitioned between 30 mL of diethyl ether and 25 mL of saturated aqueous NaHCO3. The aqueous layer was extracted with 3 × 30 mL of diethyl ether, and the combined organic extracts were dried (MgSO4), filtered, and concentrated under reduced pressure and chromatographed (silica gel; 20:1-50:1 hexanes/EtOAc) to give the corresponding acetylenic N-Boc-amine. Method B. A solution consisting of 3.37 mmol (1.0 equiv) of the appropriate acetylenic acid in 19 mL of benzene or toluene was treated in dropwise fashion, and with vigorous stirring, with 1.0 equiv each of DPPA and triethylamine at rt under a nitrogen atmosphere. After addition was complete, the reaction mixture was heated at reflux for 3.5 h, and the solvent was evaporated under reduced pressure. The residue was taken up in 14 mL of methylene chloride containing 3.0 equiv of t-BuOH and 5% (v/v) of TMSCl, and the resulting mixture was stirred at rt under nitrogen for 10-36 h until reaction was complete (TLC). The reaction was then quenched by slow addition of 15 mL of saturated aqueous NaHCO3. The mixture was then diluted with 20 mL of diethyl ether, and the separated aqueous layer was extracted with 3 × 15 mL of diethyl ether. The combined organic extracts were dried (MgSO4), filtered, concentrated under reduced pressure, and chromatographed (silica gel; 20:1-50:1 hexanes/EtOAc) to give the corresponding acetylenic N-Boc-amine. Acetylenic Amine 28a. This material was prepared in 82% yield following method A above, employing 779 mg (5.57 mmol, 1.0 equiv) of acetylenic acid 25a, 1.20 mL (1.0 equiv) of DPPA, and 0.78 mL (1.0 equiv) of triethylamine in 32 mL of benzene for 3.5 h and 55 mg (0.1 equiv) of CuCl in 32 mL of t-BuOH for 1.25 h. Chromatography (silica gel; 20:1-50:1 hexanes/EtOAc) gave 963 mg (82%) of acetylenic amine 28a
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as a pale yellow solid: mp 46.0-47.0 °C (hexanes, colorless rectangular crystals); [R]25D +61.1° (c ) 24.8, MeOH); MS m/e 155 (M+ - 56), 144, 138, 126, 109, 96, 88, 67, 57; IR (CH2Cl2) 3429, 3302, 2974, 2112, 1708, 1503, 1455, 1367, 1232, 1164, 1095 cm-1; 1H NMR (CDCl3) δ 0.99 (t, J ) 7.0 Hz, 3H), 1.18 (d, J ) 7.0 Hz, 3H), 1.42 (s, 9H), 1.49 (m, 2H), 2.09 (d, J ) 2.5 Hz, 1H), 2.28 (m, 1H), 3.79 (m, 1H), 4.64 (d, J ) 10.0 Hz, 1H). Anal. Calcd for C12H21NO2: C, 68.21; H, 10.01; N, 6.63. Found: C, 68.12; H, 10.07; N, 6.60. Acetylenic Amine ent-28a. This material was prepared in 74% yield following method A above, employing 673 mg (4.80 mmol, 1.0 equiv) of ent-25a, 1.04 mL (1.0 equiv) of DPPA, and 0.67 mL (1.0 equiv) of triethylamine in 27 mL of benzene for 3.5 h and 48 mg (0.1 equiv) of CuCl in 27 mL of t-BuOH for 1.25 h. Chromatography (silica gel; 20:1-50:1 hexanes/ EtOAc) gave 748 mg (74%) of acetylenic amine ent-28a as a pale yellow solid: mp 46.0-47.0 °C (hexanes, colorless rectangular crystals); [R]25D -64.0° (c ) 20.1, MeOH); IR and 1H NMR are identical those of acetylenic amine 28a. Acetylenic Amine 28b. This material was prepared in 64% yield following method B above, employing 380 mg (2.46 mmol, 1.0 equiv) of acetylenic acid 25b, 0.53 mL (1.0 equiv) of DPPA, and 0.34 mL (1.0 equiv) of triethylamine in 14 mL of benzene for 3.5 h and 0.70 mL (3.0 equiv) of t-BuOH in 9.7 mL of methylene chloride containing 5% (v/v) of TMSCl for 14 h. Chromatography (silica gel; 20:1-50:1 hexanes/EtOAc) gave 357 mg (64%) of acetylenic amine 28b as a pale yellow oil: [R]25D +55.2° (c ) 20.4, MeOH); IR (CH2Cl2) 3429, 3302, 2977, 1708, 1504, 1454, 1367, 1231, 1164, 1096, 1022 cm-1; 1H NMR (CDCl ) δ 0.99 (d, J ) 6.6 Hz, 3H), 1.05 (d, J ) 6.7 3 Hz, 3H), 1.21 (d, J ) 6.6 Hz, 3H), 1.44 (S, 9H), 1.72 (m, 1H), 2.06 (m, 1H), 2.15 (d, J ) 2.4 Hz. 1H), 3.97 (m, 1H), 4.69 (bs, 1H); 13C NMR (CDCl3) δ 20.5, 20.8, 21.1, 26.2, 29.6, 45.6, 45.8, 72.4, 78.8, 82.7, 155.0; HRMS(CI) calcd for (C13H23NO2 + H) ([M + H]+) 226.1807, found 226.1799. Acetylenic Amine 28c. This material was prepared in 92% yield following method B above, employing 587 mg (2.38 mmol, 1.0 equiv) of acetylenic acid 25c, 0.51 mL (1.0 equiv) of DPPA, and 0.33 mL (1.0 equiv) of triethylamine in 14 mL of benzene for 3.5 h and 0.68 mL (3.0 equiv) of t-BuOH in 9.5 mL of methylene chloride containing 5% (v/v) of TMSCl for 18 h. Chromatography (silica gel; 20:1-50:1 hexanes/EtOAc) gave 698 mg (92%) of acetylenic amine 28c as a pale yellow solid: mp 58.0-58.5 °C (hexanes, colorless fluffy crystals); [R]25D +34.9° (c ) 19.8, MeOH); MS m/e 261 (M+ - 56), 244, 217, 183, 154, 144, 108, 91, 57; IR (CH2Cl2) 3429, 3302, 3033, 2979, 2174, 1708, 1491, 1188, 1175, 1100 cm-1; 1H NMR (CDCl3) δ 1.22 (d, J ) 6.5 Hz, 3H), 1.28 (d, J ) 6.5 Hz, 3H), 1.41 (s, 9H), 2.12 (d, J ) 2.5 Hz, 1H), 2.51 (m, 1H), 3.60 (quint, J ) 6.5 Hz, 1H), 3.94 (m, 1H), 4.53 (d, J ) 12.0 Hz, 1H), 4.62 (d, J ) 12.0 Hz, 1H), 4.83 (d, J ) 8.0 Hz, 1H), 7.31 (m, 5H). Anal. Calcd for C19H27NO3: C, 71.89; H, 8.57; N, 4.41. Found: C, 71.81; H, 8.61; N, 4.43. Acetylenic Amine ent-28c. This material was prepared in 82% yield following method B above, employing 793 mg (3.22 mmol, 1.0 equiv) of acetylenic acid ent-25c, 0.69 mL (1.0 equiv) of DPPA, and 0.45 mL (1.0 equiv) of triethylamine in 18.5 mL of benzene for 3.5 h and 0.91 mL (3.0 equiv) of t-BuOH in 12.8 mL of methylene chloride containing 5% (v/v) of TMSCl for 18 h. Chromatography (silica gel; 20:1-50:1 hexanes/ EtOAc) gave 838 mg (82%) of acetylenic amine ent-28c as a pale yellow solid: mp 58.0-58.5 °C (hexanes, colorless fluffy crystals); [R]25D -34.4° (c ) 4.7, MeOH); IR and 1H NMR are identical to those of acetylenic amine 28c. Acetylenic Amine 50a. This material was prepared in 81% yield following method B above, employing 390 mg (1.59 mmol, 1.0 equiv) of acetylenic acid 49a, 0.34 mL (1.0 equiv) of DPPA, and 0.22 mL (1.0 equiv) of triethylamine in 9.6 mL of toluene at 105 °C for 4.5 h and 0.45 mL (3.0 equiv) of t-BuOH in 6.4 mL of methylene chloride containing 5% (v/v) of TMSCl for 18 h. Chromatography (silica gel; 20:1-50:1 hexanes/ EtOAc) gave 409 mg (81%) of acetylenic amine 50a as a pale yellow solid: mp 54.5-55.0 °C (hexanes, colorless needles); [R]25D +12.8° (c ) 15.0, MeOH); IR (CH2Cl2) 3430, 3302, 3050, 2980, 1708, 1501, 1367, 1266, 1165, 1052 cm-1; 1H NMR (CDCl3) δ 1.22 (d, J ) 6.7 Hz, 3H), 1.30 (d, J ) 6.2 Hz, 3H),
Jacobi et al. 1.44 (s, 9H), 2.18 (d, J ) 2.5 Hz, 1H), 2.69 (m, 1H), 3.68 (quint, J ) 6.2 Hz, 1H), 3.86 (m, 1H), 4.52 (d, J ) 11.7 Hz, 1H), 4.66 (d, J ) 11.7 Hz, 1H), 4.99 (bs, 1H), 7.26-7.40 (m, 5H); 13C NMR (CDCl3) δ 17.4, 18.0, 28.3, 44.1, 46.9, 70.9, 72.3, 73.9, 79.0, 81.7, 127.4, 127.7, 128.2, 138.1, 154.9. Anal. Calcd for C19H27NO3: C, 71.89; H, 8.57; N, 4.41. Found: C, 71.82; H, 8.63; N, 4.40. Acetylenic Amine 50s. This material was prepared in 72% yield following method B above, employing 55.6 mg (0.23 mmol, 1.0 equiv) of acetylenic acid 49s, 0.049 mL (1.0 equiv) of DPPA, and 0.032 mL (1.0 equiv) of triethylamine in 1.4 mL of toluene at 100 °C for 4.5 h and 0.064 mL (3.0 equiv) of t-BuOH in 1 mL of methylene chloride containing 5% (v/v) of TMSCl for 11 h. Chromatography (silica gel; 20:1-50:1 hexanes/EtOAc) gave 51.5 mg (72%) of acetylenic amine 50s as a pale yellow oil: IR (CH2Cl2) 3427, 3302, 3033, 2980, 2141, 1711, 1501, 1454, 1367, 1231, 1164, 1092, 1021 cm-1; 1H NMR (CDCl3) δ 1.22 (d, J ) 6.6 Hz, 3H), 1.36 (d, J ) 6.1 Hz, 3H), 1.46 (s, 9H), 2.18 (d, J ) 2.4 Hz, 1H), 2.59 (m, 1H), 3.55 (m, 1H), 4.33 (m, 1H), 4.46 (d, J ) 10.6 Hz, 1H), 4.53 (d, J ) 10.6 Hz, 1H), 4.86 (bd, J) 9.9 Hz, 1H), 7.24-7.45 (m, 5H); HRMS(CI) calcd for (C19H27NO3 + H) ([M + H]+) 318.2069, found 318.2090. Acetylenic Amine 43. This material was prepared in 83% yield following method B above, employing 481 mg (1.18 mmol, 1.0 equiv) of acetylenic acid 42, 0.25 mL (1.0 equiv) of DPPA, and 0.17 mL (1.0 equiv) of triethylamine in 7.5 mL of toluene at 100 °C for 5 h and 1.7 mL (15.0 equiv) of t-BuOH in 4.5 mL of methylene chloride containing 5% (v/v) of TMSCl for 4 days. Chromatography (silica gel; 20:1-50:1 hexanes/EtOAc) gave 469 mg (83%) of acetylenic amine 43 as a colorless oil: [R]25D +28.1° (c ) 6.3, CH2Cl2); MS m/e 225 (M+ - 254), 211, 199, 197, 183, 181, 155, 135, 121, 105; IR (CH2Cl2) 3429, 3302, 3073, 2963, 2933, 2860, 2139, 1712, 1504, 1428, 1392, 1367, 1236, 1172, 1112 cm-1; 1H NMR (CDCl3) δ 1.03 (t, J ) 7.5 Hz, 3H), 1.06 (s, 9H), 1.43 (s, 9H), 1.57 (m, 2H), 1.59 (d, J ) 1.5 Hz, 1H), 1.82 (m, 2H), 2.48 (m, 1H), 3.64-3.81 (m, 2H), 3.91 (m, 1H), 4.70 (d, J ) 10.0 Hz, 1H), 7.34-7.70 (m, 10H). Anal. Calcd for C29H41NO3Si: C, 72.61; H, 8.61; N, 2.92. Found: C, 72.44; H, 8.68; N, 3.20. Acetylenic Amine 60. This material was prepared in 75% yield following method B above, employing 697 mg (1.35 mmol, 1.0 equiv) of acetylenic acid 59, 0.29 mL (1.0 equiv) of DPPA, and 0.19 mL (1.0 equiv) of triethylamine in 8.4 mL of toluene at 100 °C for 4.5 h and 1.3 mL (10.0 equiv) of t-BuOH in 5.5 mL of methylene chloride containing 5% (v/v) of TMSCl for 16 h. Chromatography (silica gel; 20:1-50:1 hexanes/EtOAc) gave 597 mg (75%) of acetylenic amine 60 as a pale yellow oil: [R]25D +20.8° (c ) 6.8, CH2Cl2); IR (CH2Cl2) 3427, 3302, 3072, 2931, 1711, 1501, 1366, 1172, 1112, 1067 cm-1; 1H NMR (CDCl3) δ 1.08 (s, 9H), 1.32 (d, J ) 6.1 Hz, 3H), 1.43 (s, 9H), 2.16 (d, J ) 2.5 Hz, 1H), 2.82 (m, 1H), 3.71 (m, 2H), 3.80 (m, 1H), 3.98 (m, 1H), 4.51 (d, J ) 11.7 Hz, 1H), 4.66 (d, J ) 11.7 Hz, 1H), 5.13 (d, J ) 8.7 Hz, 1H), 7.25-7.69 (m, 15H); 13C NMR (CDCl3) δ 17.8, 19.2, 26.9, 28.4, 34.0, 43.2, 49.4, 61.3, 71.0, 72.3, 73.7, 78.9, 82.0, 127.5, 127.6, 127.9, 128.3, 129.6, 133.4, 133.5, 135.5, 138.4, 155.4; HRMS(CI) calcd for (C36H47O4Si + H) ([M+ + H]) 586.3354, found 586.3339. General Procedures for the Oxidative Cleavage of the Acetylenic Bond. Method A. A solution of 2.47 mmol (1.0 equiv) of the appropriate acetylenic N-Boc-amine in 58 mL of t-BuOH was treated in dropwise fashion, and with vigorous stirring, with a solution consisting of 0.3 equiv of KMnO4, 6.0 equiv of NaIO4, and 5.0 equiv of NaHCO3 in 58 mL of water. After being stirred at rt for 3 h, the reaction mixture was treated with 8.1 mL of ethanol, and the resulting mixture was filtered through Celite and washed with 145 mL of 50% aqueous t-BuOH. The filtrate was concentrated to about 90 mL, acidified with 122 mL of 10% aqueous acetic acid, and extracted with 6 × 80 mL of ethyl acetate. The extracts were dried (MgSO4) and concentrated under reduced pressure, and the residue was taken up in 50 mL of benzene. The benzene was concentrated again under reduced pressure to remove any traces of acetic acid. The remaining residue was dissolved in 8 mL of THF and 8 mL of 15% aqueous KOH and stirred at rt for 2.5 h to cleave any N-formyl substituent. The reaction
Total Syntheses of Thienamycin and PS-5 mixture was then acidified to pH ) 2 with 5 N aqueous HCl and extracted with 6 × 35 mL of ethyl acetate. The combined organic extracts were dried (MgSO4), filtered, concentrated under reduced pressure, and chromatographed (silica gel; 75: 25:0.3 hexanes/EtOAc/HOAc) to afford the corresponding carboxylic acid. Method B. A solution of 2.10 mmol (1.0 equiv) of the appropriate acetylenic N-Boc-amine in 12 mL of THF and 12 mL of water was treated portionwise, with vigorous stirring, with 103 mg (0.2 equiv) of OsO4 at rt to give a dark reaction mixture. After addition was complete (∼5 min), the reaction was treated with 6.0 equiv of NaIO4, and the mixture immediately turned light yellow in color. After the mixture was stirred for 3 days, an additional 1.5 equiv of NaIO4 was added and stirring was continued until reaction was complete (TLC; 2-3 days). The reaction mixture was then diluted with 50 mL of water and extracted with 6 × 50 mL of ethyl acetate. The combined extracts were dried (MgSO4), filtered, and concentrated under reduced pressure to give a dark sticky oil. This material was dissolved in 11 mL of THF and 2.4 mL of water and was treated with 1.0 equiv of NaIO4 for 5 min to give a bright yellow solution. This solution was then treated with 10 mL of 15% aqueous KOH, and the resulting mixture was stirred at rt for 1.5 h to cleave the N-formyl substituent. The THF was then removed under reduced pressure, and the remaining aqueous solution was diluted with 24 mL of water, washed with 3 × 40 mL of methylene chloride, acidified to pH ) 2 with 5 N aqueous HCl, and extracted with 6 × 40 mL of ethyl acetate. The combined extracts were dried (MgSO4), filtered, concentrated under reduced pressure, and chromatographed (silica gel; 75:25:0.3 hexanes/EtOAc/HOAc) to afford the corresponding carboxylic acid. β-Amino Acid 30a. This material was prepared in 97% yield following method A above, employing 522 mg (2.47 mmol, 1.0 equiv) of acetylenic amine 28a in 58 mL of t-BuOH, a solution consisting of 0.72 mmol (0.3 equiv) of KMnO4, 14.7 mmol (6.0 equiv) of NaIO4, and 12.2 mmol (5.0 equiv) of NaHCO3 in 58 mL of water at rt for 3 h, and a solution of 8 mL of THF and 8 mL of 15% aqueous KOH at rt for 2.5 h. Chromatography (silica gel; 75:25:0.3 hexanes/EtOAc/HOAc) afforded 554 mg (97%) of β-amino acid 30a as a white solid: mp 72.0-74.0 °C (hexanes, colorless fluffy crystals); [R]25D +12.7° (c ) 2.7, MeOH); MS m/e 158 (M+ - 73), 144, 116, 98, 88, 73, 57; IR (CH2Cl2) 3433, 3500-2350, 1706, 1504, 1368, 1165 cm-1; 1H NMR (CDCl3) δ 0.98 (t, J ) 7.4 Hz,3H), 1.19 (d, J ) 6.8 Hz, 3H), 1.44 (s, 9H), 1.61 (m, 1H), 1.71 (m, 1H), 2.41 (m, 1H), 3.97 (m, 1H), 5.20 (bd, J ) 10.0 Hz, 1H). Anal. Calcd for C11H21NO4: C, 57.12; H, 9.15; N, 6.06. Found: C, 57.16; H, 9.18; N, 6.08. β-Amino Acid ent-30a. This material was prepared in 92% yield following method A above, employing 722 mg (3.42 mmol, 1.0 equiv) of acetylenic amine ent-28a in 80 mL of t-BuOH, a solution consisting of 1.01 mmol (0.3 equiv) of KMnO4, 20.3 mmol (6.0 equiv) of NaIO4, and 16.9 mmol (5.0 equiv) of NaHCO3 in 80 mL of water at rt for 2.5 h, and a solution of 12 mL of THF and 10 mL of 15% aqueous KOH at rt for 2 h. Chromatography (silica gel; 75:25:0.3 hexanes/EtOAc/HOAc) afforded 724 mg (92%) of β-amino acid ent-30a as a white solid: mp 72.0-74.0 °C (hexanes, colorless fluffy crystals); [R]25D -13.8° (c ) 7.2, MeOH); IR and 1HNMR are identical to those of β-amino acid 30a. β-Amino Acid 30b. This material was prepared in 86% yield following method A above, employing 348 mg (1.54 mmol, 1.0 equiv) of acetylenic amine 28b in 37 mL of t-BuOH, a solution consisting of 0.46 mmol (0.3 equiv) of KMnO4, 9.25 mmol (6.0 equiv) of NaIO4, and 7.71 mmol (5.0 equiv) of NaHCO3 in 37 mL of water at rt for 3 h, and a solution of 5 mL of THF and 5 mL of 15% aqueous KOH at rt for 2.5 h. Chromatography (silica gel; 75:25:0.3 hexanes/EtOAc/HOAc) afforded 326 mg (86%) of β-amino acid 30b as a colorless oil: [R]25D +23.8° (c ) 15.1, MeOH); IR (CH2Cl2) 3430, 3430-2425, 1703, 1504, 1368, 1234, 1166, 1098 cm-1; 1H NMR (CDCl3) δ 0.90 (d, J ) 6.4 Hz, 3H), 0.92 (d, J ) 6.8 Hz, 3H), 1.09 (d, J ) 6.8 Hz, 3H), 1.36 (s, 9H), 1.90 (m, 1H), 2.05 (dd, J ) 4.5, 10.0 Hz, 1H), 3.99 (m, 1H), 5.32 (d, J ) 10.0 Hz, 1H); 13C NMR (CDCl3) δ 20.2, 20.5, 21.0, 28.0, 28.3, 44.4, 57.3, 79.3, 155.6,
J. Org. Chem., Vol. 61, No. 7, 1996 2425 179.7; HRMS(CI) calcd for (C12H23NO4 + H) ([M + H]+) 246.1706, found 246.1708. β-Amino Acid 30c. This material was prepared in 68% yield following method B above, employing 297 mg (0.94 mmol, 1.0 equiv) of acetylenic amine 28c in 4 mL of THF and 4 mL of water, 52 mg (0.2 equiv) of OsO4, and 2.20 g (11.0 equiv) of NaIO4 for 6 days at rt. After cleavage, chromatography (silica gel; 75:25:0.3 hexanes/EtOAc/HOAc) afforded 215 mg (68%) of β-amino acid 30c as a colorless oil: [R]25D +62.4° (c ) 16.3, MeOH); IR (CH2Cl2) 3429, 3429-2538, 1707, 1502, 1368, 1163, 1088 cm-1; 1H NMR (CDCl3) δ 1.20 (d, J ) 6.7 Hz, 3H), 1.34 (d, J ) 7.0 Hz, 3H), 1.44 (m, 9H), 2.60 (dd, J ) 4.0, 9.0 Hz, 1H), 3.86 (m, 1H), 4.04 (m, 1H), 4.42 (d, J ) 11.5 Hz, 1H), 4.64 (d, J ) 11.5 Hz, 1H), 5.33 (d, J ) 10.0 Hz, 1H), 7.30 (m, 5H); HRMS(CI) calcd for (C18H27NO5 + H) ([M + H]+) 338.1968, found 338.1986. β-Amino Acid ent-30c. This material was prepared in 68% yield following method B above, employing 665 mg (2.10 mmol, 1.0 equiv) of acetylenic amine ent-28c in 12 mL of THF and 12 mL of water, 103 mg (0.2 equiv) of OsO4, and 4.93 g (11.0 equiv) of NaIO4 for 6 days at rt. After cleavage, chromatography (silica gel; 75:25:0.3 hexanes/EtOAc/HOAc) afforded 482 mg (68%) of β-amino acid ent-30c as a colorless oil: [R]25D -64.7° (c ) 12.8, MeOH); IR and 1H NMR are identical to those of compound β-amino acid 30c. β-Amino Acid 51a. This material was prepared in 71% yield following method B above, employing 696 mg (2.19 mmol, 1.0 equiv) of acetylenic amine 50a in 12.5 mL of THF and 12.5 mL of water, 99 mg (0.2 equiv) of OsO4, and 5.16 g (11.0 equiv) of NaIO4 for 6 days at rt. After cleavage, chromatography (silica gel; 75:25:0.3 hexanes/EtOAc/HOAc) afforded 527 mg (71%) of β-amino acid 51a as a white solid: mp 81.0-82.0 °C (15:1 hexanes/diethyl ether, colorless cotton-like crystals); [R]25D +14.7° (c ) 19.8, MeOH); IR (CH2Cl2) 3431, 3431-2500, 1750, 1710, 1503, 1455, 1392, 1368, 1237 cm-1; 1H NMR (CDCl3) δ 1.20 (d, J ) 6.2 Hz, 3H), 1.34 (d, J ) 5.1 Hz, 3H), 2.73 (m, 1H), 3.88 (m, 1H), 4.06 (m, 1H), 4.51 (d, J ) 11.2 Hz, 1H), 4.66 (d, J ) 11.2 Hz, 1H), 5.02 (d, J ) 8.5 Hz, 1H), 7.237.45 (m, 5H). Anal. Calcd for C18H27NO5: C, 64.07; H, 8.07; N, 4.15. Found: C, 64.10; H, 8.10; N, 4.12. β-Amino Acid 51s. This material was prepared in 57% yield following method B above, employing 49 mg (0.15 mmol, 1.0 equiv) of acetylenic amine 50s in 1 mL of THF and 1 mL of water, 11 mg (0.3 equiv) of OsO4, and 361 mg (11.0 equiv) of NaIO4 for 6 days at rt. After cleavage, chromatography (silica gel; 75:25:0.3 hexanes/EtOAc/HOAc) afforded 29 mg (57%) of β-amino acid 51s as a colorless oil: IR (CH2Cl2) 3430, 3430-2500, 1709, 1501, 1367, 1166, 1095, 1038 cm-1; 1H NMR (CDCl3) δ 1.19 (d, J ) 6.8 Hz,3H), 1.27 (d, J ) 6.2 Hz, 3H), 1.44 (s, 9H), 2.64 (bd, J ) 6.5 Hz, 1H), 3.88 (m, 1H), 4.33 (m, 1H), 4.45 (d, J ) 10.8 Hz, 1H), 4.55 (d, J ) 10.8 Hz, 1H), 5.57 (bs, 1H), 7.25-7.43 (m, 5H). β-Amino Acid 44. This material was prepared in 91% yield following method A above, employing 361 mg (0.75 mmol, 1.0 equiv) of acetylenic amine 43 in 19 mL of t-BuOH, a solution consisting of 0.22 mmol (0.3 equiv) of KMnO4, 4.51 mmol (6.0 equiv) of NaIO4, and 3.76 mmol (5.0 equiv) of NaHCO3 in 19 mL of water at rt for 6 h, and a solution of 6 mL of THF and 3 mL of 15% aqueous KOH at rt for 2.5 h. Chromatography (silica gel; 75:25:0.3 hexanes/EtOAc/HOAc) afforded 342 mg (91%) of β-amino acid 44 as a colorless oil: [R]25D +7.5° (c ) 5.1, CH2Cl2); IR (CH2Cl2) 3430, 3400-2500, 3073, 2969, 2932, 2857, 1707, 1504, 1468, 1392, 1367, 1242, 1170, 1111 cm-1; 1H NMR (CDCl ) δ 1.00 (t, J ) 7.4 Hz, 3H), 1.06 (s, 9H), 1.42 3 (s, 9H), 1.55-1.83 (m, 4H), 2.58 (m, 1H), 3.73 (m, 2H), 4.05 (m, 1H), 5.19 (d, J ) 8.6 Hz, 1H), 7.35-7.70 (m, 10H); 13CNMR (CDCl3) δ 12.1, 19.1, 22.6, 26.9, 28.4, 36.5, 48.5, 50.7, 61.1, 79.1, 127.7, 129.7, 133.5, 133.6, 135.3, 135.5, 155.7, 179.9. HRMS(FAB) calcd for (C28H41NO5Si + H) ([M + H]+) 500.2832, found 500.2844. β-Amino Acid 61. This material was prepared in 71% yield following method B above, employing 410 mg (0.70 mmol, 1.0 equiv) of acetylenic amine 60 in 4.2 mL of THF and 4.2 mL of water, 37 mg (0.2 equiv) of OsO4, and 1.65 g (11.0 equiv) of NaIO4 for 6 days at rt. After cleavage, chromatography (silica gel; 75:25:0.3 hexanes/EtOAc/HOAc) afforded 302 mg (71%)
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of β-amino acid 61 as a colorless oil: [R]25D -1.3° (c ) 17.4, CH2Cl2); IR (CH2Cl2) 3430, 3500-2500, 1753, 1712, 1656, 1501, 1368, 1169, 1111 cm-1; 1H NMR (CDCl3) δ 1.06 (s, 9H), 1.37 (d, J ) 6.1 Hz, 3H), 1.44 (s, 9H), 1.69 (m, 1H), 1.84 (m, 1H), 2.85 (bt, J ) 6.0 Hz, 1H), 3.68 (m, 1H), 3.80 (m, 1H), 3.92 (m, 1H), 4.21 (m, 1H), 4.52 (d, J ) 10.9 Hz, 1H), 4.66 (d, J ) 10.9 Hz, 1H), 5.23 (d, J ) 8.8 Hz, 1H), 7.26-7.68 (m, 15); HRMS(CI) calcd for (C35H47NO6Si + H) ([M + H]+) 606.3252, found 606.3253. General Procedure for the Cyclization of β-Amino Acids. A solution of 0.85 mmol (1.0 equiv) of the appropriate β-amino acid derivative in 16 mL of trifluoroacetic acid (TFA) was kept at 0 °C for 20 min under nitrogen to cleave the t-BOC protecting group. The reaction was then concentrated under reduced pressure, and the residue was concentrated once more from 30 mL of dry benzene to remove any remaining TFA. The resulting oil was dissolved in 60 mL of acetonitrile and was treated sequentially with 3.0 equiv of triethylamine and 2.2 equiv of dicyclohexylcarbodiimide (DCC) at rt. The reaction mixture was then stirred at 65-68 °C for 5 h, cooled to rt, and concentrated under reduced pressure. The residue was dissolved in a small amount of diethyl ether and filtered to remove suspended material (thorough washing with ether). The filtrate was then concentrated under reduced pressure and chromatographed (silica gel; 7:3 hexanes/EtOAc) to give the corresponding β-lactam. β-Lactam 32a. This material was prepared in 71% yield following the general procedure described above, employing 198 mg (0.85 mmol, 1.0 equiv) of β-amino acid derivative 30a, 16 mL of trifluoroacetic acid, 60 mL of acetonitrile, 0.36 mL (3.0 equiv) of triethylamine, and 388 mg (2.2 equiv) of dicyclohexylcarbodiimide at 65-68 °C for 5 h. Chromatography (silica gel; 7:3 hexanes/EtOAc) afforded 68 mg (71%) of 32a as a pale yellow oil: [R]25D +19.8° (c ) 10.3, CH2Cl2); IR (CH2Cl2) 3408, 2968, 1754, 1462, 1382, 1272, 1181 cm-1; 1H NMR (CDCl3) δ 0.96 (t, J ) 7.4 Hz, 3H), 1.30 (d, J ) 6.4 Hz, 3H), 1.61 (m, 1H), 1.74 (m, 1H), 2.61 (bt, J ) 6.8 Hz, 1H), 3.40 (dq, J ) 2.0, 6.1 Hz, 1H), 6.58 (bs, 1H); 13C NMR (CDCl3) δ 11.3, 20.6, 21.2, 50.2, 59.4, 171.3; HRMS(CI) calcd for (C6H11NO + H) ([M + H]+) 114.0920, found 114.0923. β-Lactam ent-32a. This material was prepared in 81% yield following the general procedure described above, employing 201 mg (0.87 mmol, 1.0 equiv) of β-amino acid derivative ent-30a, 16 mL of trifluoroacetic acid, 70 mL of acetonitrile, 0.36 mL (3.0 equiv) of triethylamine, and 361 mg (2.0 equiv) of dicyclohexylcarbodiimide at 65-68 °C for 5 h. Chromatography (silica gel; 7:3 hexanes/EtOAc) afforded 80 mg (81%) of ent-32a as a pale yellow oil: [R]25D -18.3° (c ) 19.5, CH2Cl2); IR and 1HNMR are identical to those of β-lactam 32a. β-Lactam 32b. This material was prepared in 82% yield following the general procedure described above, employing 320 mg (1.30 mmol, 1.0 equiv) of β-amino acid derivative 30b, 25 mL of trifluoroacetic acid, 91 mL of acetonitrile, 0.55 mL (3.0 equiv) of triethylamine, and 592 mg (2.2 equiv) of dicyclohexylcarbodiimide at 65-68 °C for 5 h. Chromatography (silica gel; 7:3 hexanes/EtOAc) afforded 136 mg (82%) of 32b as a pale yellow solid: mp 37.0-38.0 °C (diethyl ether, colorless cubes); [R]25D +11.3° (c ) 23.0, CH2Cl2); IR (CH2Cl2) 3407, 2965, 1751, 1468, 1368, 1274, 1173, 1053 cm-1; 1H NMR (CDCl3) δ 1.00 (d, J ) 6.8 Hz, 3H), 1.08 (d, J ) 6.4 Hz, 3H), 1.36 (d, J ) 6.3 Hz, 3H), 2.01 (octet, J ) 7.0 Hz, 1H), 2.53 (bd, J ) 8.2 Hz, 1H), 3.52 (dt, J ) 1.4, 7.0 Hz, 1H); 13C NMR (CDCl3) δ 19.8, 20.1, 20.6, 27.6, 48.4, 64.7, 170.8. Anal. Calcd for C7H13NO: C, 66.11; H, 10.35; N, 11.01. Found: C, 66.26; H, 10.35; N, 10.93. β-Lactam 32c. This material was prepared in 76% yield following the general procedure described above, employing 448 mg (1.33 mmol, 1.0 equiv) of β-amino acid derivative 30c, 25 mL of trifluoroacetic acid, 93 mL of acetonitrile, 0.56 mL (3.0 equiv) of triethylamine, and 603 mg (2.2 equiv) of dicyclohexylcarbodiimide at 65-68 °C for 5.5 h. Chromatography (silica gel; 7:3 hexanes/EtOAc) afforded 220 mg (76%) of 32c as a pale yellow oil: [R]25D +35.5° (c ) 19.8, CH2Cl2); MS m/e 176 (M+ - 43), 161, 128, 113, 98, 91, 69; IR (CH2Cl2) 3408, 3033, 2974, 1759, 1375, 1186, 1099, 1055 cm-1; 1H NMR (CDCl3) δ 1.30 (d, J ) 6.5 Hz, 3H), 1.32 (d, J ) 6.1 Hz, 3H),
Jacobi et al. 2.97 (dd, J ) 2.0, 5.0 Hz, 1H), 3.70 (dq, J ) 2.0, 6.1 Hz, 1H), 3.85 (quint, J ) 6.0 Hz, 1H), 4.50 (d, J ) 12.0 Hz, 1H), 4.62 (d, J ) 12.0 Hz, 1H), 6.04 (bs, 1H), 7.24-7.32 (m, 5H); 13C NMR (CDCl3) δ 16.7, 20.3, 46.1, 62.6, 70.4, 71.1, 127.4, 128.1, 138.2, 168.6; HRMS(CI) calcd for (C13H17NO2 + H) ([M + H]+) 220.1338, found 220.1346. β-Lactam ent-32c. This material was prepared in 83% yield following the general procedure described above, employing 386 mg (1.14 mmol, 1.0 equiv) of β-amino acid derivative ent-30c, 21 mL of trifluoroacetic acid, 81 mL of acetonitrile, 0.48 mL (3.0 equiv) of triethylamine, and 520 mg (2.2 equiv) of dicyclohexylcarbodiimide at 65-68 °C for 5 h. Chromatography (silica gel; 7:3 hexanes/EtOAc) afforded 208 mg (83%) of ent-32c as a pale yellow oil: [R]25D -36.5° (c ) 10.5, CH2Cl2); IR and 1H NMR are identical to those of β-lactam 32c. β-Lactam 53. This material was prepared in 61% yield following the general procedure described above, employing 53 mg (0.16 mmol, 1.0 equiv) of β-amino acid derivative 51, 3 mL of trifluoroacetic acid, 22 mL of acetonitrile, 0.066 mL (3.0 equiv) of triethylamine, and 71 mg (2.2 equiv) of dicyclohexylcarbodiimide at 65-68 °C for 8 h. Chromatography (silica gel; 7:3 hexanes/EtOAc) afforded 21 mg (61%) of 53 as a pale yellow oil: [R]25D -56.8° (c ) 11.4, CH2Cl2); IR (CH2Cl2) 3407, 3034, 2977, 1759, 1381, 1060 cm-1; 1H NMR (CDCl3) δ 1.32 (d, J ) 6.4 Hz, 3H), 1.36 (d, J ) 6.3 Hz, 3H), 3.24 (m, 1H), 3.80 (m, 2H), 4.52 (d, J ) 11.8 Hz, 1H), 4.67 (d, J ) 11.8 Hz, 1H), 6.39 (bs, 1H), 7.23-7.39 (m, 5H); 13C NMR (CDCl3) δ 16.2, 18.8, 47.2, 58.6, 70.2, 71.0, 127.3, 127.5, 128.2, 138.4, 168.8; HRMS(CI) calcd for (C13H17NO2 + H) ([M + H]+) 220.1338, found 220.1342. β-Lactam 54. Method A. This material was prepared in 70% yield following the general procedure described above, employing 29 mg (0.09 mmol, 1.0 equiv) of β-amino acid derivative 48s, 1.6 mL of trifluoroacetic acid, 12 mL of acetonitrile, 0.036 mL (3.0 equiv) of triethylamine, and 38 mg (2.2 equiv) of dicyclohexylcarbodiimide at 65-68 °C for 5 h. Chromatography (silica gel; diethyl ether) afforded 13 mg (70%) of 54 having identical chemical and physical properties as described below in method B. Method B: Epimerization of β-Lactam 53. A solution of 27 mg (0.12 mmol, 1.0 equiv) of β-lactam 53 in 0.5 mL of dry methylene chloride was stirred at rt under nitrogen and was treated with 0.052 mL (3.0 equiv) of triethylamine and 0.059 mL (2.5 equiv) of trimethylsilyl triflate. After the mixture was stirred for 3 h, the reaction was treated with 1 mL of 1 N aqueous hydrogen chloride and 0.5 mL of THF. The resulting mixture was stirred at rt for 1.5 h, diluted with 1 mL of water and 1 mL of saturated aqueous NaHCO3, and extracted with 3 × 6 mL of methylene chloride and 6 mL of diethyl ether. The combined organic extracts were dried (MgSO4), filtered, concentrated under reduced pressure, and chromatographed (silica gel; diethyl ether) to afford 20 mg (74%) of 54 as a pale yellow oil: [R]25D -26.4° (c ) 7.7, CH2Cl2); IR (CH2Cl2) 3408, 3033, 2974, 1761, 1496, 1454, 1381, 1348, 1274, 1197, 1160, 1096, 1055 cm-1; 1H NMR (CDCl3) δ 1.31 (d, J ) 6.2 Hz, 3H), 1.38 (d, J ) 6.2 Hz, 3H), 2.81 (dd, J ) 2.0, 6.4 Hz, 1H), 3.73 (dq, J ) 1.9, 6.1 Hz, 1H), 3.89 (quint, J ) 6.3 Hz, 1H), 4.51 (d, J ) 11.7 Hz, 1H), 4.64 (d, J ) 11.7 Hz, 1H), 6.21 (bs, 1H), 7.25-7.36 (m, 5H); 13CNMR (CDCl3) δ 18.1, 20.8, 48.0, 64.0, 70.6, 72.3, 127.5, 128.2, 138.4, 168.4; HRMS(CI) calcd for (C13H17NO2 + H) ([M + H]+) 220.1338, found 220.1342. β-Lactam 33. This material was prepared in 91% yield following the general procedure described above, employing 213 mg (0.43 mmol, 1.0 equiv) of β-amino acid derivative 44, 8.4 mL of trifluoroacetic acid, 30 mL of acetonitrile, 0.018 mL (3.0 equiv) of triethylamine, and 191 mg (2.2 equiv) of dicyclohexylcarbodiimide at 70 °C for 5 h. Chromatography (silica gel; 7:3 hexanes/EtOAc) afforded 147 mg (91%) of 33 as a colorless oil: [R]25D +11.8° (c ) 6.6, CH2Cl2); MS m/e 281 (M+ - 100), 254, 224, 199, 183, 181, 176, 135, 105, 77; IR (CH2Cl2) 3406, 3072, 2962, 2933, 2860, 1755, 1472, 1428, 1388, 1362, 1188, 1112 cm-1; 1H NMR (CDCl3) δ 1.02 (m, 3H), 1.07 (s, 9H), 1.66-1.87 (m, 4H), 2.75 (m, 1H), 3.47 (m, 1H), 3.74 (m, 2H), 5.74 (bs, 1H), 7.38-7.68, (m, 10H); 13C NMR (CDCl3) δ 11.3, 19.1, 21.4, 26.9, 37.5, 52.7, 58.4, 61.9, 170.8.19a
Total Syntheses of Thienamycin and PS-5 β-Lactam 62. This material was prepared in 56% yield following the general procedure described above, employing 153 mg (0.25 mmol, 1.0 equiv) of β-amino acid derivative 61, 5 mL of trifluoroacetic acid, 35 mL of acetonitrile, 0.11 mL (3.0 equiv) of triethylamine, and 115 mg (2.2 equiv) of dicyclohexylcarbodiimide at 65-68 °C for 10 h. Chromatography (silica gel; 7:3 hexanes/EtOAc) afforded 68 mg (56%) of 62 as a pale yellow oil: [R]25D -24.6° (c ) 12.2, CH2Cl2); IR (CH2Cl2) 3406, 3071, 2932, 1758, 1389, 1112 cm-1; 1H NMR (CDCl3) δ 1.04 (s, 9H), 1.37 (d, J ) 6.4 Hz, 3H), 1.81 (m, 1H), 2.02 (m, 1H), 3.27 (m, 1H), 3.70 (m, 2H), 3.80 (m, 2H), 4.43 (d, J ) 11.9 Hz, 1H), 4.65 (d, J ) 11.9 Hz, 1H), 5.87 (bs, 1H), 7.21-7.66 (m, 15H); 13C NMR (CDCl3) δ 18.5, 19.1, 26.9, 32.8, 50.1, 58.7, 62.3, 70.0, 70.6, 127.3, 127.5, 127.7, 128.2, 128.4, 129.8, 133.1, 133.2, 135.4, 138.2, 168.3; HRMS(CI) calcd for (C30H37NO3Si + H) ([M + H]+) 488.2622, found 488.2639. β-Lactam 63. A solution of 59 mg (0.12 mmol, 1.0 equiv) of β-lactam 62 in 0.5 mL of dry methylene chloride was stirred at rt under nitrogen and was treated with 0.05 mL (3.0 equiv) of triethylamine and 0.06 mL (2.5 equiv) of trimethylsilyl triflate. After the mixture was stirred for 3.5 h, the reaction was treated with 1 mL of 1 N aqueous hydrogen chloride and 0.5 mL of THF. The resulting mixture was stirred at rt for 1.5 h, diluted with 1 mL of water and 1 mL of saturated aqueous NaHCO3, and extracted with 3 × 6 mL of methylene chloride and 6 mL of diethyl ether. The combined organic extracts were dried (MgSO4), filtered, concentrated under
J. Org. Chem., Vol. 61, No. 7, 1996 2427 reduced pressure, and chromatographed (silica gel; 1:1 hexanes/EtOAc) to afford 39 mg (66%) of 63 as a pale yellow oil: [R]25D -1.9° (c ) 6.3, CH2Cl2); IR (CH2Cl2) 3414, 3072, 2932, 1753, 1472, 1428, 1112 cm-1; 1H NMR (CDCl3) δ 1.04 (s, 9H), 1.27 (d, J ) 6.2 Hz, 3H), 1.79 (m, 1H), 1.88 (m, 1H), 2.85 (dd, J ) 1.5, 5.9 Hz, 1H), 3.74 (m, 3H), 3.87 (quint, J ) 6.2 Hz, 1H), 4.48 (d, J ) 11.7 Hz, 1H), 4.61 (d, J ) 11.7 Hz, 1H), 5.78 (bs, 1H), 7.24-7.65 (m, 15H); 13C NMR (CDCl3) δ 18.2, 19.1, 26.9, 37.5, 50.4, 62.0, 62.8, 70.7, 72.2, 127.5, 127.8, 128.3, 129.78, 129.82, 133.2, 135.4, 138.4, 168.2; HRMS(CI) calcd for (C30H37NO3Si + H) ([M + H]+) 488.2622, found 488.2628.12e,22
Acknowledgment. Financial support of this work by the National Science Foundation, Grant Nos. CHE9001485 and CHE-9424476, is gratefully acknowledged. Supporting Information Available: Copies of 1H and 13C NMR spectra for compounds 24a-c, 25a-c, 27c, 28a-c, 30ac, 32a-c, 33, 39, 40, 42, 43a, 44, 49a, 49s, 50a, 50s, 51a, 51s, 53, 54, 56, 57, and 59-63 (31 pages). This material is contained in libraries on microfiche, immediately follows this article in the microfilm version of the journal, and can be ordered from the ACS; see any current masthead page for ordering information. JO952092U
